One wandering pitch set up Carlos Villanueva's first loss in nearly two years.
Miguel Cairo hit a two-run homer in the sixth off Villanueva, stopping Cincinnati's streak of 16 scoreless innings, and the Reds got their first win over an American League team this season, beating the Toronto Blue Jays 2-1 on Sunday.
The Reds had dropped their previous five interleague games against Cleveland and Toronto.
Bronson Arroyo (6-6) ended his streak of dismal days against the Blue Jays. The right-hander gave up five hits, including Aaron Hill's homer, in a season-high eight innings. Arroyo had lost his last three starts and five straight decisions against Toronto.
Villanueva (4-1) lost for the first time since Aug. 17, 2009, with Milwaukee, where he was a reliever the last two years. He'd made 84 appearances without taking a loss, a streak that didn't mean much to him because most of those were in relief.
"I didn't even really know that until you guys started talking about it," he told reporters. "As a reliever, wins and losses are more luck sometimes, especially wins. I'll take a game like this anytime over a game where I throw five innings and give up six runs and get a win."
One bad pitch was too much for the Blue Jays to overcome against Arroyo and Francisco Cordero, who pitched the ninth for his 15th save in 17 tries. The closer moved one ahead of Jeff Montgomery for sole possession of 19th on the career list with 305 saves. Hall of Famer Goose Gossage is next at 310.
First baseman Joey Votto had three hits, after failing to reach base in the first two games of a special series. The Toronto native received the Lou Marsh Trophy before Saturday's game honoring him as Canada's top athlete for 2010.
He singled with one out in the sixth and came around on Cairo's homer down the left-field line on a fastball that was up and over the inside half of the plate — not where it was supposed to go. Cairo was in the lineup at third base for Scott Rolen, who was getting a day to rest.
"It was supposed to go away there," Villanueva said. "If I get it in the away lane, he's not going to hit a home run to the opposite field. We had the right idea, it was just a little bit of a mistake."
The homer ended a streak of 16 scoreless innings by the NL's most prolific offense. The Reds lost the series opener 3-2, getting a pair of solo homers, and were blanked 4-0 on Saturday.
Villanueva gave up seven hits in seven innings and didn't walk a batter.
"He certainly pitched well enough," Toronto manager John Farrell said. "Most days, that's a very good chance to come away with a win."
The Blue Jays have hit Arroyo hard. He gave up a career-high 10 runs while retiring a career-low three batters during a 14-1 loss at Toronto in 2008. A year later, he went back to Toronto and gave up seven runs in 3 2-3 innings of an 8-2 loss.
This time, he had only one shaky inning. Hill led off the fifth with a homer, and the Blue Jays got a runner thrown out at third on a safety squeeze play to scuttle the rally.
Juan Rivera singled after Hill's homer and took third on J.P. Arencibia's single with none out. Farrell decided to try the safety squeeze, but John McDonald popped up the bunt attempt. Votto caught it and threw to third to double up Rivera.
"You go from runners at first and third with nobody out to all of a sudden a quick zero," Farrell said. "It seemed to shift the momentum a little bit at that point."
During their 4-0 win on Saturday night, Blue Jays outfielder Corey Patterson was tagged out at third after he incorrectly thought the ball had gone out of play, thwarting a rally.
NOTES: Blue Jays SS Yunel Escobar agreed to a two-year, $10 million contract before the game. He gets $5 million each of the next two years. There are two club options for $5 million as well. ... The Blue Jays go to Atlanta next for three games. The Reds have a three-game home series against the Yankees, making their first visit since 2003. ... Arroyo is 3-5 against Toronto in 12 career starts.