If you were staying in one of Pinellas' other beach communities, it wouldn't be too bad for a one-day thing, but Clearwater adds a whole extra layer of traffic complexity because of the extra water crossing. Traffic especially tends to back up on the Clearwater Causeway Bridge between downtown Clearwater and Clearwater Beach, but it also can get slow on the Courtney Campbell between downtown Clearwater and the Tampa mainland. If you're definitely going to do it, be sure to leave REALLY early in the morning, well before the normal summer beach traffic starts; as in, before dawn, and don't go back until at least 10 pm.
Beyond the bridges, the wild card in this equation is I-4. If traffic is clear, it's about 90 minutes from the Tampa airport exit on I-275 to the Osceola Parkway exit on I-4, but traffic is essentially NEVER clear on this route anymore, except in the wee hours of the morning. (I did the RT drive 2 years ago between midnite and 2am; long story why. Even then, we hit a tiny slowdown just north of Davenport.) There are bottleneck spots on I-4 between Tampa and WDW almost every day, and if there is a wreck then all bets are off; it can easily take 4 hours one-way when that happens.
Doing the RT run once in a trip isn't too bad, so I'd suggest that if you need to save money on your car rental or flights by flying both ways from the same airport (right now the usually free one-way rental car dropoff within Florida is not happening), then it's not that big a deal to backtrack to the other city in order to spend a few days at either the beginning or end of your trip, but it's really a PITA to repeatedly battle commuting traffic to spend long enough days at WDW to get your money's worth.