The Mariners are 6-14 in extra-inning games and have lost 26 games in their opponent's final at-bat.
LaFromboise, a rookie left-hander pitching just his ninth game in the Majors, entered with one out and two on in the 10th and got a double-play grounder from Josh Hamilton.
But LaFromboise gave up a one-out single in the 11th to Kole Calhoun, whom Iannetta drove in with a two-out shot off the center-field fence to end the game after four hours, 10 minutes.
LaFromboise grew up in Downey, Calif., about 20 minutes from Angel Stadium, and had more than 50 family and friends in the stands. With the Mariners' bullpen running thin late in the season, manager Eric Wedge stuck with the 27-year-old southpaw after he had already used five pitchers.
"Any time you're in extra innings, you become a long guy," said LaFromboise. "I knew I needed to go in there and get outs, righties and lefties, and prove I can do it. For the most part, except for one pitch [to Iannetta], I thought I did pretty good. Even that pitch, I don't regret throwing. It was something different. He'd seen five fastballs. I threw it, and it wasn't a great location and he made me pay for it."
With Charlie Furbush, Yoervis Medina and Tom Wilhelmsen unavailable because of heavy use recently, Wedge had limited options as the game wore on.
"We used a lot of guys tonight to try to hold them off," Wedge said. "The bullpen has had their issues here late, being worn down and being late and in these situations for the first time in September. I thought they did a real nice job tonight."
Mariners right-hander Erasmo Ramirez threw six-plus innings with only two unearned runs marring his night after the Angels took advantage of a Kyle Seager throwing error to tie the game at 2 in the seventh.
Michael Saunders staked Seattle to a lead with a two-run single in the top of the seventh before the Angels quickly rallied.
Seattle's pitchers had been tormented at Angel Stadium in two prior series this season, getting outscored by 43-16 while winning just once in six games. But Ramirez reversed that trend with six scoreless innings until Seager's error and a walk put two runners on in the seventh.
Trainer Rick Griffin then went out to the mound with Wedge and pitching coach Carl Willis, and Ramirez was removed after feeling tightness in his right groin muscle.
The Angels sacrificed both runners into scoring position, and Andrew Romine delivered a tying two-run single off reliever Chance Ruffin to leave Ramirez with a tough no-decision.
Seager entered the game only after pinch-hitting in the top of the seventh, having had his string of consecutive starts ended at 106 when he was given most of the night off, then committed the error on the first ball hit to him.
"Kyle was ready to go," Wedge said. "He makes that play all the time, but it's a tough play right off the bat. He's coming in, he's down, he's got to come up and throw it across. He just got underneath the throw a little bit."
Ramirez, who missed the first three months of the season with a sore elbow, remained 5-2 while lowering his ERA to 4.56. He was coming off his shortest start of the season, a four-inning outing at St. Louis when he gave up eight hits and five runs in four innings, but was much sharper against the Angels while walking one and striking out three.
The Mariners were blanked for the first five innings by Angels right-hander Matt Shoemaker in his Major League debut, managing just two hits and two walks before manager Mike Scioscia went to his bullpen after the 26-year-old had thrown 93 pitches.
Seattle's leadoff runner reached base in the second, fifth and sixth innings -- including a double by Saunders in the sixth -- but failed to score each time as the Mariners finished 2-for-14 with runners in scoring position.
"We were one hit away quite a bit, and that's been an issue for us, just these kids being up there in that situation," Wedge said. "It takes time. You see the veterans in Anaheim's lineup compared to us, and that's just where we are with our youth."
Saunders continued a recent offensive surge, as a double and a walk were included in the center fielder's 2-for-4 night. Saunders has hit .466 (7-for-15) with four doubles and a triple over his last four games.
Nick Franklin was 3-for-5 with a double and played an excellent shortstop in his first start there.