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If the 66 I-6 was like most ford cylinder heads, then induction hardened seats probably werent taken into consideration, if that is true, hardened seats should be considered, should you rebuild that head.
Externally, the '80 will have more mounts for various emmissions gizmos.
Internally, the '66 may have slightly different combustion chambers (size), it won't have hardened valve seats, & the piston pins will be a smaller size (same size as the 351).
Those should be the major differences.
Edwin
Both engines are carbureted, so I can't think of too many differences. The 300 block stayed the same for the most part throughout its 30 year casting run. An '80 wouldn't have any extra mounts for emissions equipment, because the only emissions device that bolts to the block (as opposed to EGR, etc) is a smog pump, which shares the mounting with the alternator as far as I know. I guess there could be minor differences, so it'd be good to check. My main concern would be making sure the flywheels match.
In reference to the last post - why would the pistons be a different size? All 300's have a 4 inch bore. And what 351 are you talking about? Ford made 3 different 351's, it's important you specify. If you meant the 351M, then that has a 4 inch bore as well and the bores are indeed the same. Unless you're talking about compression, which I would imagine there'd be differences there like you said.
Sorry, the 351W has a different size (smaller) piston pin than the 300. '65-69(?) 240/300 used the same size pin, later motors use a larger diameter pin.