Planning our next vacation (Spain/Italy/France)!

This past November we visited parts of Spain over 2 1/2 weeks, including Madrid and San Sebastian (Donostia). Madrid is definitely vibrant and I'd highly recomend it, but part of its attraction for us was its outstanding art museums, including the Prado, Reina Sofia, and Thyssen-Bornemisza. It might be a shame to miss Madrid if it fit into your travel schedule and was on your way, but not a crime :-)

Donostia is reachable by plane, train, bus, or rental car. We stayed there for 2 nights and also visited Bilbao (with another outstanding museum, which might not appeal to you) an hour to the west. The tapas dinner scene and the crowds and music in the square in Donostia midday on Sunday were lively, even in November, so October shouldn't dampen things. It did pour rain one day, however, and spit rain a few other times, and the locals toted umbrellas. The aquarium there was great, though, and got us out of the rain. Again, October could be better, but take at least a jacket and prepare to wear layers for warmth in the fall. The underground parking garages cost about 25 euros a day, so if you're driving, that's an additional expense.

Seems a rather ambitious plan for 3 weeks. You could spend all that time on the Italy portion alone and wish you had more time.

Seems I may need to drop either the Cote D'Azur or the Amalfi Coast...which would you drop? I've read the Amalfi Coast is more spread out so may be more difficult to see in 3-4 days. But getting there may be easier since we'll already be in Italy than getting from Cote D'Azur to Florence?

For travel connections, what do you think of the following:
-Fly into Madrid from the USA
-Train from Madrid to Seville
-Train from Seville to Barcelona (flying would be faster but might be more hassle with the wheelchair)

Option 1 (includes Cote D'Azur)
-Fly from Barcelona to Nice (I think train would take way too much time plus multiple connections)
-Fly or train from Nice to Florence/Pisa/Siena? This is a difficult one.

Option 2 (includes Amalfi Coast)
-Fly (or take a boat?) from Barcelona to Florence (Livorno?)/Pisa?
-Rent a car for a few days to drive through Tuscany.
-Car or train from Florence/Siena to Naples (then take ferry to Sorrento?)?
-Train from Naples to Rome
-Fly from Rome to USA

With a wheelchair in mind and most efficient time wise, what do you think would be our best travel options for getting from place to place?

We were based in Sorrento for a few days over New Year's 2012/2013 and drove the Amalfi coast in our Europcar rental car, as well as driving to Pompeii, Herculaneum, and other sights near Naples. We took the train to go into Naples for a day, however. A ferry was never considered there, although we used the short ferry ride to get from Sicily onto the mainland with our car earlier in the week. Flying from Barcelona would be a lot faster than going by boat, especially if the seas were rough. If going by car on the Autostrada, though, you should be able to pick up a rental car in one Italian city and return it in another without problems -- we picked up in Palermo and returned in Sorrento, and there were no extra fees for doing that.

There are budget airlines (like Vueling) that can jet you quickly and cheaply, but they can have severe luggage restrictions, fees, and policies (read the fine print), and sometimes the planes are on the small side, which might or might not present accessibility issues for the person with the wheelchair. You mentioned confusion before at the airport - was that dealing with the wheelchair at the security checkpoint, or wheeling through the terminal on the way to the gate? Hopefully you all (including the companion in the wheelchair) won't encounter any difficulties this time around!

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Nice, Cannes, Marseilles, Provence...so many choices. Where would you
suggest?

I suggest Provence, which may work a little better with Catalonia than the Cote d'Azure.