Wade scored 32 points and O'Neal added 25 as the Heat shot 55 percent en route to their 10th straight home win, a 108-100 triumph over the 76ers.
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76ers-Heat: 300k 
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"It's a huge task guarding Shaquille," Sixers coach Jim O'Brien said. "We executed a great game plan last time when we beat them (January 24 in Philadelphia). I wasn't pleased with the way we challenged shots. In fact, I wasn't pleased with anything."
The Heat, who led by as many as 22 points in the second half, made 39-of-71 shots overall.
"We cannot win if we play defense like that," Sixers guard Allen Iverson said. "No way, no way we win this game with defense like that. Tonight, they were hitting everything, even when we were challenging. We just couldn't stop them."
Wade frequently blew past his initial defender and got fouled in the lane. He set career highs in free throws attempted (23) and made (18), with the latter besting the franchise mark of Alonzo Mourning, who was ejected with 26 seconds left for picking up two technicals for a brief confrontation with Philadelphia's Samuel Dalembert.
"I was just trying to attack," Wade said. "I knew that Iverson was going to be doing that, and I was just trying to do the same thing. I think I did a good job of that. ... I got back into my attack mode tonight. I just wanted to get into the lane and mix things up a bit."
"(Wade's) playing good, he's keeping everyone involved, he's shooting the ball good, he's leading us and that's what a great guard does," O'Neal said.
Miami, which was playing its fourth contest in five nights, won its sixth straight as it moved a season-high 30 games over .500 (46-16). The Heat, who have not lost at AmericanAirlines Arena since an overtime setback to Indiana on January 21, were beginning a seven-game stretch in which they play here six times.
"When you look at the fact that you play four games in five days, three of them against playoff teams, we had a little fatigue set in in the fourth quarter tonight," Miami coach Stan Van Gundy said. "But I was pretty happy with the way we played tonight."
Miami is an Eastern Conference-best 25-5 at home.
"It's a fabulous place to play," O'Neal said. "Our fans have been here all year. We want this to be a place where teams know it will be a tough place to get a win."
The reigning Eastern Conference Player of the Week, Iverson scored 27 points and Dalembert chipped in 21 for the Sixers (29-31), who were hoping to improve to .500 for the first time since February 14.
"I thought we did a good job on Allen Iverson, but the guy's incredible," Van Gundy said. "He still had 27."
But O'Neal was even better. In the third quarter he scored 15 points as Miami opened a 91-71 cushion entering the final period.
"Philadelphia loads everyone up on Shaq, so other people get very easy, very wide open shots," Van Gundy said. "He was running the floor, and he really worked to get the ball, which you have to do against Philadelphia. You can not just stand there and get the ball.
"The flipside is that when you can get Shaq the ball, it is over the top and it is just dunks. But he really got the ball deep in the third quarter and just took over."
Iverson said that adding O'Neal has made Wade much more dangerous.
"Not taking anything away from Dwyane, he's great and a special player, but when you've got that guy on the floor with you it makes everything that much easier," Iverson said. "You can't play (Shaq) with one man, you've got to try to play him with all five men, but you can't play defense with all five men (on one guy) in this league."
Chris Webber added 10 points for Philadelphia, which slipped to 3-3 since acquiring the forward in a blockbuster deal with Sacramento on February 23. Webber shot just 4-of-13 for the Sixers, who connected on 46 percent (39-of-71).
"We clearly didn't have what it takes to win tonight against a quality team," O'Brien said. "They have a lot of quality players. Wade is terrific the way he gets people involved. They were too much for us."