I actually have had issues with games not liking my ps/2 mouse--Space Quest IV, King's Quest V, and Laura Bow II (all editions from the "Collection Series" box sets, I don't have different releases to test against except in SQ4's case tho I never did test).
The sitch with those is strange. In both an older machine and my current rig (different motherboard and processor but the sound and video card are both from the older rig) had this issue where in those games sound effects wouldn't work/would cause the games to glitch or lock up unless I disabled the CPU Cache AND set the SFX card type to "Thunderboard" (I don't even know what a Thunderboard is but the install said it was a valid option). This was all well and good but once I started using a ps/2 mouse the games would always lock up with it, but if I plugged in the serial mouse they were just fine.
And yes, I tried the various alternate drivers/fan-made patches that exist including the one that basically turns SQ4 into the floppy version. Those didn't help. Oddly tho the games play just fine in Dosbox, so that's what I wound up doing for them. Nobody has ever been able to come up with an explanation for this situation, tho I'm suspecting something to do with drivers, IRQ, or those three games being hipsters who only like serial mice.
But because Dosbox worked I always considered this a minor issue at best. Still thought it was worth bringing up.
As it happens I've pretty much decided--at least for the time being--that I will just go with a serial mouse and ordered another Q500 Optical Mouse (the one I currently have has an over-sensitive left-click. It seems like I should be able to fix this but I'm unwilling to risk breaking it until I have a replacement lined up, which is actually why I'm reluctant to repair the mobo too). I'd love to get a Mouse Systems PC Mouse but those all go for stupid expensive prices on ebay and other online retailers and then a lot of them are ps/2 as well. Basically, the one scruple I have is I won't use a ball mouse--I hate how they seem to always get hung up on things and don't roll smoothly, always at times where I need to point only a pixel to the side.
One reason I DO eventually want to repair the ps/2 ports tho, is simply ease of replacability--if a ps/2 mouse goes bad I can find lots of dozens on ebay for a low price, but serial stuff is hard to find and I'm not sure I could mod/repair it to make it more durable, especially since I'm kinda/sorta a complete idiot and klutz.
Anyway, yeah, now that you've heard my story I wonder if anyone has more thoughts about the SQ4/KQ5/LB2 issue.