One DOS application I use was hurt by this: "old DOS OrCAD". It works well in Windows-XP on a 32-bit machine, but does not work at all in 64-bit Windows. (It's actually a 32-bit DPMI program and has drivers to use Windows GDI so you don't have to mess around with drivers).
More evidence: IBM 360 mainframe software still works in Z/OS.
It might be worth it for non-generic computing devices like cell phones, but Intel missed the boat there already.