Both of A-Rod's home runs came off Ledezma, giving him four homers in four career at-bats against the left-hander.
"I think it's pretty obvious that he's comfortable against him," Tigers manager Alan Trammell.
Rodriguez, who leads the major leagues with 16 homers and 46 RBI, was plunked near the hip by Franklyn German in the seventh, a pitch that appeared to be intentional.
"You have to pitch inside. It was a sinker that moved too much. I didn't want to hit him. What can you do?" German said.
A-Rod jogged to first without a problem, but was removed from the game just as several other Yankees regulars already had been.
"I don't want to talk about it, so many good things happened tonight," Rodriguez said. "It feels like I got stung pretty good."
Paul Quantrill retaliated in the eighth, throwing behind Jason Smith and then hitting him with a pitch in the back. That brought the Tigers out of their dugout, and Quantrill egged them on, gesturing for them to come out for a fight.
"If they want to come out on the field and chirp, then just come out to the mound," Quantrill said. "When guys get wild when our guys are having a fantastic day at the plate, that leads to tension. The guy pitching for the Tigers, whatever his name is, it must have been the rain, the ball was slippery."
The Yankees never left their bench, and order was quickly restored with no punches thrown. New York manager Joe Torre and Quantrill were ejected.
"I lost a lot of respect for him," Detroit's Rondell White said. "You don't throw, trying to hit somebody up near his head, and then do that. It was terrible. We wanted him to know we didn't like it."
Quantrill said the Yankees didn't appreciate that play and thought it was "out of line," but the latest tension between the teams seemed to stem more from Rodriguez getting plunked and Quantrill throwing high.
Robinson Cano hit his first major league homer and Gary Sheffield also connected, showing his sore left hand is healthy enough for him to hit. The Yankees (24-21) finished with a season-high six home runs, four off Ledezma, and won for the 13th time in 15 games to pull 1½ games behind second-place Boston in the AL East.
Mussina (5-2) allowed six hits in seven shutout innings, winning his fourth straight decision in a span of five starts. He improved to 16-5 against the Tigers.
"It's good to see us come out after the off day and keep the momentum going," Mussina said. "The last two years I got off to a little bit of a slow start and I've been able to figure things out five or six starts into the season. We're playing more like we thought we would, more like we think we're capable of."
Even on a windy, 48-degree night in the Bronx, New York's hitters warmed up quickly, scoring 10 or more runs for the seventh time this season.
Posada homered from both sides of the plate for the sixth time in his career and drove in four runs. Rodriguez had the 39th multihomer game of his career, the third this season. He also walked, scored three times and knocked in three runs.
Rodriguez homered to right-center off Ledezma (2-4) in the second and added a two-run shot in the fourth. Posada followed with a drive to left, his first homer from the right side this season. Jason Giambi then singled, Bernie Williams doubled and Cano delivered a sacrifice fly, making it 5-0.
Sheffield hit a two-run shot in the fifth for No. 422 of his career, chasing Ledezma. Hideki Matsui doubled off Matt Ginter, Rodriguez walked and Posada connected for a three-run homer from the left side and a 10-0 lead.
Cano homered into the right-field upper deck off Doug Creek in the bottom half.
- Sheffield missed the previous two games because of tendinitis in his left hand.
- Rodriguez has 397 career homers.
- The Yankees have won five consecutive series openers.
- New York's Tony Womack got his 15th stolen base, 12 in the last 10 games without being caught.
- For sitting through the cold, rainy weather, the Yankees offered fans a chance to exchange their ticket stubs for free admission to a game on Sept. 6 or Sept. 8 against Tampa Bay.
- The four homers allowed were a career high for Ledezma.
- It was Posada's 10th career multihomer game.
- The six homers by New York tied its most ever at Yankee Stadium, accomplished four times previously. The previous was June 4 last year against Texas.
- The Yankees are 26-8 against Detroit at home since the start of the 1998 season.
- New York starting pitchers are 12-1 with a 2.78 ERA in the last 15 games. They were 8-14 with a 5.48 ERA in the first 30 games.