Iwakuma gave up a leadoff homer to Nick Markakis, and that turned out to be the game's only run in Seattle's 1-0 loss to the Baltimore Orioles on Sunday.
The Mariners had never lost 1-0 when the lone run came on a leadoff homer. It was just the ninth time in franchise history they dropped a 1-0 game in which the only run was a home run.
"The first home run, the first hitter in the first inning, cost me the whole game," Iwakuma said through a translator. "When (you) look at it at the end, it's tough like that."
Iwakuma (9-6) was outstanding, allowing only one run on five hits in 7 2-3 innings. He struck out seven and walked two.
Baltimore's Chris Tillman (8-5) was even better.
He blanked Seattle on three hits over seven innings, striking out six and walking none. A second-round draft pick by Seattle in 2006, Tillman is 6-0 in six career starts against the Mariners.
Newcomer Andrew Miller worked a perfect eighth and Zach Britton got three outs for his 23rd save.
It was the first time in Orioles history that they won 1-0 on a leadoff homer.
"That was cool. That was interesting," Tillman said. "Their pitcher was good. I knew runs were going to be at a premium today; just a matter of battling through at-bats."
Iwakuma lost on the road for the first time in 15 starts since July 4, 2013. He was 9-0 over that span.
"One pitch in his first seven pitches," Seattle catcher Mike Zunino said. "Other than that, I thought he was excellent."
Iwakuma's most glaring error came against Markakis, who hit a shot to right on a 3-2 pitch. Markakis had three hits and now has 1,501 for his career. He came within a triple of hitting for the cycle.
"I hope everybody understands what we're watching here," Baltimore manager Buck Showalter said. "We talk about some of those guys through the years that were solid Orioles, you've got to mention his name, hopefully for many years."
The victory was the ninth in 13 games for the AL East-leading Orioles, who won the season series from Seattle 5-2.
Seattle put runners on the corners with one out in the second before Tillman struck out Zunino and Brad Miller. That began a run of 14 straight outs by Tillman, a streak that ended when Kendrys Morales singled leading off the seventh.
Kyle Seager then hit into a 4-6-3 double play.
The Mariners now have Monday off. They return to action against the Braves on Tuesday at Safeco Field.