diff -r 1addc5d2c246 Doc/whatsnew/3.6.rst
--- a/Doc/whatsnew/3.6.rst	Tue Nov 22 23:04:39 2016 +0100
+++ b/Doc/whatsnew/3.6.rst	Thu Nov 24 00:53:40 2016 +0100
@@ -2220,6 +2220,10 @@ Changes in the Python API
 Changes in the C API
 --------------------
 
+* The ``f_lasti`` field of the frames (:c:type:`PyFrameObject`) is now
+  initialized to ``-2`` instead of ``-1`` to work better with the new bytecode
+  format using 16-bit units. (:issue:`28782`).
+
 * The :c:func:`PyMem_Malloc` allocator family now uses the :ref:`pymalloc allocator
   <pymalloc>` rather than the system :c:func:`malloc`. Applications calling
   :c:func:`PyMem_Malloc` without holding the GIL can now crash. Set the
diff -r 1addc5d2c246 Objects/frameobject.c
--- a/Objects/frameobject.c	Tue Nov 22 23:04:39 2016 +0100
+++ b/Objects/frameobject.c	Thu Nov 24 00:53:40 2016 +0100
@@ -14,11 +14,21 @@ static PyMemberDef frame_memberlist[] = 
     {"f_code",          T_OBJECT,       OFF(f_code),      READONLY},
     {"f_builtins",      T_OBJECT,       OFF(f_builtins),  READONLY},
     {"f_globals",       T_OBJECT,       OFF(f_globals),   READONLY},
-    {"f_lasti",         T_INT,          OFF(f_lasti),     READONLY},
     {NULL}      /* Sentinel */
 };
 
 static PyObject *
+frame_getlasti(PyFrameObject *f, void *closure)
+{
+    int lasti = f->f_lasti;
+    if (lasti < 0) {
+        /* replace -2 with -1 for backward compatibility with Python 3.5 */
+        lasti = -1;
+    }
+    return PyLong_FromLong(lasti);
+}
+
+static PyObject *
 frame_getlocals(PyFrameObject *f, void *closure)
 {
     if (PyFrame_FastToLocalsWithError(f) < 0)
@@ -354,6 +364,7 @@ frame_settrace(PyFrameObject *f, PyObjec
 
 
 static PyGetSetDef frame_getsetlist[] = {
+    {"f_lasti",         (getter)frame_getlasti, NULL, NULL},
     {"f_locals",        (getter)frame_getlocals, NULL, NULL},
     {"f_lineno",        (getter)frame_getlineno,
                     (setter)frame_setlineno, NULL},
@@ -721,7 +732,7 @@ PyFrame_New(PyThreadState *tstate, PyCod
         f->f_locals = locals;
     }
 
-    f->f_lasti = -1;
+    f->f_lasti = -(int)sizeof(_Py_CODEUNIT);
     f->f_lineno = code->co_firstlineno;
     f->f_iblock = 0;
     f->f_executing = 0;
diff -r 1addc5d2c246 Objects/genobject.c
--- a/Objects/genobject.c	Tue Nov 22 23:04:39 2016 +0100
+++ b/Objects/genobject.c	Thu Nov 24 00:53:40 2016 +0100
@@ -63,7 +63,7 @@ void
        issue a RuntimeWarning. */
     if (gen->gi_code != NULL &&
         ((PyCodeObject *)gen->gi_code)->co_flags & CO_COROUTINE &&
-        gen->gi_frame->f_lasti == -1) {
+        gen->gi_frame->f_lasti < 0) {
         if (!error_value) {
             PyErr_WarnFormat(PyExc_RuntimeWarning, 1,
                              "coroutine '%.50S' was never awaited",
@@ -158,7 +158,7 @@ gen_send_ex(PyGenObject *gen, PyObject *
         return NULL;
     }
 
-    if (f->f_lasti == -1) {
+    if (f->f_lasti < 0) {
         if (arg && arg != Py_None) {
             char *msg = "can't send non-None value to a "
                         "just-started generator";
@@ -463,6 +463,7 @@ static PyObject *
             assert(ret == yf);
             Py_DECREF(ret);
             /* Termination repetition of YIELD_FROM */
+            assert(gen->gi_frame->f_lasti >= 0);
             gen->gi_frame->f_lasti += sizeof(_Py_CODEUNIT);
             if (_PyGen_FetchStopIterationValue(&val) == 0) {
                 ret = gen_send_ex(gen, val, 0, 0);
diff -r 1addc5d2c246 Python/ceval.c
--- a/Python/ceval.c	Tue Nov 22 23:04:39 2016 +0100
+++ b/Python/ceval.c	Thu Nov 24 00:53:40 2016 +0100
@@ -1053,8 +1053,8 @@ PyObject* _Py_HOT_FUNCTION
     assert(_Py_IS_ALIGNED(PyBytes_AS_STRING(co->co_code), sizeof(_Py_CODEUNIT)));
     first_instr = (_Py_CODEUNIT *) PyBytes_AS_STRING(co->co_code);
     /*
-       f->f_lasti refers to the index of the last instruction,
-       unless it's -1 in which case next_instr should be first_instr.
+       f->f_lasti refers to the index of the last instruction, unless it's
+       negative in which case next_instr should be first_instr.
 
        YIELD_FROM sets f_lasti to itself, in order to repeatedly yield
        multiple values.
@@ -1067,12 +1067,10 @@ PyObject* _Py_HOT_FUNCTION
        FOR_ITER is effectively a single opcode and f->f_lasti will point
        to the beginning of the combined pair.)
     */
-    assert(f->f_lasti >= -1);
+    assert(f->f_lasti >= -(int)sizeof(_Py_CODEUNIT));
     next_instr = first_instr;
-    if (f->f_lasti >= 0) {
-        assert(f->f_lasti % sizeof(_Py_CODEUNIT) == 0);
-        next_instr += f->f_lasti / sizeof(_Py_CODEUNIT) + 1;
-    }
+    assert((f->f_lasti + sizeof(_Py_CODEUNIT)) % sizeof(_Py_CODEUNIT) == 0);
+    next_instr += (f->f_lasti + sizeof(_Py_CODEUNIT)) / sizeof(_Py_CODEUNIT);
     stack_pointer = f->f_stacktop;
     assert(stack_pointer != NULL);
     f->f_stacktop = NULL;       /* remains NULL unless yield suspends frame */
@@ -2049,6 +2047,7 @@ PyObject* _Py_HOT_FUNCTION
             f->f_stacktop = stack_pointer;
             why = WHY_YIELD;
             /* and repeat... */
+            assert(f->f_lasti >= (int)sizeof(_Py_CODEUNIT));
             f->f_lasti -= sizeof(_Py_CODEUNIT);
             goto fast_yield;
         }