Catcher J.P. Arencibia backed up Romero's six effective innings with a three-run homer and the Toronto Blue Jays beat the Red Sox 7-4 on Thursday night.
Romero came in 2-6 with an 8.08 ERA in 11 career starts against the Red Sox, including an 0-3 record and 10.62 ERA in five home starts.
From the first inning on, he established his curveball because Boston had been staying away from his change-up.
"I used (my curveball) a lot," Romero said. "That was part of our game plan to come in and get that established right away from the first inning and for the rest of the game."
Romero (14-10) held Boston to five hits, three walks and three runs while striking out seven in 6 2/3 innings. All the runs against him came in the seventh.
"I felt like I had good control of my fastball and my sinker," Romero said. "And you know when you add a change-up and a curveball you add two pitches in their heads and now you're kind of able to make more pitches and keep them off-balance."
Edwin Encarnacion and Eric Thames also hit solo shots for the Blue Jays and Jason Varitek homered in the ninth for Boston against Frank Francisco.
"We kept throwing the fastball and throwing his hook," Arencibia said. "If they're going to eliminate the change-up we're going to go somewhere else and his fastball was good enough to stay with it and his ball was really sinking and the hook was good, so when we started dropping change-up in there it was that much better."
September call-up David Cooper had three hits, including two doubles, and two runs batted in.
Varitek hit his 11th homer Francisco, who entered in the ninth to protect a four-run lead.
An error by second baseman Kelly Johnson and Marco Scutaro's single gave the Red Sox hope with two out in the ninth. But Dustin Pedroia struck out to end the game.
Andrew Miller (6-3) allowed five runs and eight hits including homers by Arencibia and Encarnacion over five innings. Michael Bowden allowed Thames' homer in the seventh.
"I think at times when they hurt me I was behind in the count," Romero said of his past against Boston. "I felt like at times I was trying to trick them and show pitches and try to kind of nibble at times.
"Today I kind of just went with my instincts. J.P. and I had a great game plan and we stuck to it all night and it worked."
Romero breezed through his first six innings but had some trouble in the seventh as Boston scored three runs.
Varitek walked with one out, Darnell McDonald had a two-out infield hit and Jacoby Ellsbury drove in a run with a double. Casey Janssen replaced Romero and gave up Scutaro's two-run single.
Scutaro finished the series 11-for-17.
Thames got one run back with his 10th homer in the seventh. Brett Lawrie of Langley. B.C. and Cooper hit consecutive one-out doubles in the eighth against Felix Doubront to bump the lead to four.
Arencibia's 22nd homer was the fourth hit in a row to start the second for the Blue Jays (72-72). Johnson led off with an infield hit and Lawrie drove a single through the right side on a hit and run.
Cooper looped a sweeping breaking ball to left to score the first run. Arencibia followed by clubbing a 3-2 changeup deep to left for a 4-0 Toronto lead.
Encarnacion, who drove in five runs in Wednesday's 11-10 victory over the Red Sox (85-58), hit his 16th homer of the season, a drive to right, on a 3-1 fastball in the third.
Neither team could do anything with their respective leadoff doubles in the first. Ellsbury led off the game with a double. Then, in a mystifying move, Scutaro, who was 8-for-13 in the first three games of the series, sacrificed the runner to third.
"He was just trying to move him any way he could," Red Sox manager Terry Francona said.
Romero struck out Dustin Pedroia and retired David Ortiz on a grounder to end the inning.
Yunel Escobar started the bottom of the first with a double, but Scutaro was involved in all three outs at shortstop, two of them strong plays. He grabbed an over-the-shoulder catch on a bloop by Thames and a smart grab and throw on a hard grounder by Encarnacion.
Notes: Attendance at Rogers Centre was 17,189. ... Dustin McGowan will start Sunday for the Blue Jays against Baltimore instead of Luis Perez who returns to the bullpen. McGowan came back from two shoulder surgeries and made his first major-league outing since July 8, 2008 when he pitched four innings of relief on Tuesday. ... First baseman Adam Lind rested a sore right wrist for the second game in a row on Thursday. ... Centre fielder Colby Rasmus took live batting on Thursday afternoon for the first time since injuring his right wrist on Aug. 23. ... Brett Cecil (4-8, 4.60 ERA) opens a three-game series against Baltimore on Friday when he faces Jeremy Guthrie (6-17, 4.45 ERA).