In 1999, Mamiya modified their decades-old 645 system to include an important feature; autofocus. On top of this massive change, Mamiya revamped their body design as well, bringing the camera fully into the modern age.

645AF cameras retain the interchangeable film backs of earlier manual bodies, but lose the ability to swap prisms and finders. All 645AF cameras have an electronically-controlled focal plane shutter with speeds from 30s to 1/4000s. The size, shape, and features of 645AF cameras make them an easy transition from 35mm (or a DSLR) to medium format.

Manual focus lenses for earlier Mamiya 645 cameras will work on 645AF cameras, but AF lenses cannot be used on manual focus bodies. Manual focus lenses can also only be used in stop-down mode, and will not work on modern Phase One XF digital bodies unless modified.