BOSTON — Grady Sizemore chuckled just a bit when he was told Tuesday night’s walk-off hit was his first since 2006.

“Oh, gosh, a long time ago,” the veteran outfielder, trying to write a nifty comeback story with Boston, said after his long RBI single in the 12th inning gave the Red Sox a 4-3 victory over the Cincinnati Reds in the opener of a two-game interleague series.

Sizemore, once a star center fielder with the Cleveland Indians, is back in the majors after missing the past two seasons with back and knee problems — and playing a total of just 104 games in 2010 and ’11. Last winter, he chose the Red Sox over the Reds, and Tuesday night he crossed what his manager, John Farrell, called another “first” off the comeback list.

“Nights like tonight go a long way to continue to rebuild Grady,” Farrell said after the Red Sox (16-17) won for the third time in four games to get to within a game of the elusive .500 mark again. “To walk things off, I gotta believe tonight gives him even further feeling that he’s contributing here rather than being someone coming back from an injury.”

Sizemore, usually calm on the field, clearly was in a mood to celebrate this one.

“I was pretty excited,” he said. “It was a good feeling. I try not to get too emotional out there, try to keep it on the same level, but right there I let it out a little bit.”

Sizemore is platooning with Jonny Gomes in left field and appears to be coming around at the plate. This is a process, and he took a major step Tuesday.

He also continued his career assault on the Reds, improving his lifetime average against Cincinnati to .319 by going 3-for-6.

Designated hitter David Ortiz, playing in his 2,000th major league game, opened the 12th win a single off Logan Ondrusek (0-2), and he moved up on first baseman Mike Napoli’s single. Ortiz seemed to be looking into the dugout for a pinch runner, but it didn’t matter as Sizemore then came through with a long drive off the wall in left-center, scoring Ortiz from second.

It was the fourth walk-off hit of Sizemore’s career.

Boston left-hander Craig Breslow (1-0) pitched the top of the 12th, striking out two.

Red Sox closer Koji Uehara pitched out of trouble in the ninth, when Cincinnati rookie catcher Tucker Barnhart hit one almost 380 feet that was run down by right fielder Shane Victorino — a ball that would be a home run in warmer weather or in most ballparks.

Left-hander Andrew Miller struck out four in two scoreless innings before Breslow came on.

The Reds, making their second visit to Fenway Park since winning the classic 1975 World Series, tied the game with two runs off right-hander Junichi Tazawa in the eighth. A walk, a double by second baseman Brandon Phillips, an RBI single by third baseman Todd Frazier and a sacrifice fly by left fielder Ryan Ludwick leveled the score at 3-3.

“We finally got something going a little late,” said Ludwick, who added, “Any time you lose a game, you think about missed opportunities.”

The Reds, who have eight players on the disabled list and several others nursing minor injuries, lost for the sixth time in 10 games. They fell to 15-17.

“These guys don’t want sorrow from anybody.” manager Bryan Price said. “It is what it is. There are other teams that get a little banged up. These guys are great. These guys are gamers. These are guys who are a little beat up who are going out there and playing anyway.

“I admire them for that. I’m proud of them for that. That being said, we’re not going to lower our standards and expectations and say, ‘We’re not supposed to win against the better team because we’re banged up.’ This is a disappointing loss, a game that was winnable and we didn’t win it.”

Napoli drove in two runs for the Red Sox, while second baseman Dustin Pedroia had three hits, including the 299th and 300th doubles of his career.

Boston left-hander Felix Doubront, who hasn’t won since his first start, left with a 3-1 lead after working 5 1/3 innings. However, the bullpen blow a lead for the second time in his six-start drought.

Reds starter Homer Bailey pitched six innings, allowing three runs.

The Red Sox will again try to get back to the .500 mark in the series finale Wednesday night. Since losing the fifth game of the season to fall to 2-3, Boston has had five chances to reach .500 and failed all five times.