You are much better off in terms of comfort and efficiency having two systems versus one. You may want to put in dampers to control the lower and main floors. The area is large enough to warrant it.

Around here, that house would get 3 systems. I am not sure that is necessary or the most cost effective solution.

But there are lots of options and you have to give a better idea of your priorities. It is install cost, ongoing costs, comfort etc? Is this forced air throughout? Do you have NG?

The number of systems is not necessarily the first choice. FWIW - I have 2 systems in a similar house. So far it is working well but I just finished the walkout.

Going to 1 system allows that system to be the best - 96% furnace with heat pump. The only problem in your setting is that the top floor is so much smaller than the second that short cycling of your a/c at night might be an issue with some systems. Even with Infinity running at low stage, that upstairs will get cold really fast and not dehumidify well. But if the design was really good, it might all work. What you would want is do dump some onto the first floor even though the Infinity technically doesn't allow that.

All-in-all, you would need a really slick installer to get 1 system to work well. Most around here would put 3 basic systems in. Often a basic system costs less than the upgrade to a good zoned system (ie 2 basic systems cost less that 1 zoned system). At 3 floors, while the zone system would seem to get cheaper (vs 3 units), the complexity of design goes up significantly.

Get 2 systems. A basic one for the upstairs (that might not be used all the time?), and a really good zoned system for the 1st 2 floors.

Thanks for the good feedback,

It will be a natural gas system, forced air throughout. My objectives are comfort, quiet, efficiency and ease of maintenance in the future. I'm willing to spend the dollars up front, but I want to make sure that I do everything right.

If you want to do it right, then you need to find a good HVAC contractor who will do Manual J calculation and proper duct sizing. You want a system which will provide even temperture distribution thoughout all rooms.