That means losing their designated hitter on the road, of course, which in Seattle's case isn't as large an issue as it used to be in the Edgar Martinez days. Manager Eric Wedge has rotated the DH this season, particularly in the past two weeks, with rookie catcher Jesus Montero getting more time behind the plate while Miguel Olivo is on the disabled list.
The bigger issue will be pitchers picking up the bats and trying their luck. But Seattle's first Interleague starter is no stranger to that situation. Kevin Millwood is slated to throw Friday's series opener at Colorado and he's a long-time National League veteran with 467 career at-bats.
Millwood has hit .122 with four home runs and 27 RBIs. The 37-year-old is no stranger to Interleague Play, where he's 15-14 with a 4.91 ERA in 40 career starts.
Jason Vargas follows on Saturday and he's the Mariners' best hitting pitcher, with a .250 average in 56 career at-bats. Blake Beavan, who throws Sunday, has never pitched in an Interleague road game and will be batting for the first time in his pro career.
Players to watch
Felix Hernandez, RHP (12-6, 2.85 ERA): The King loves hitting in Interleague road games, but for some reason, opponents are slightly more worried about his pitching.
Jason Vargas, LHP (5-4, 2.96 ERA): Vargas has held opposing hitters to a .244 average in Interleague Play, which is lower than his own career batting average of .250 in 56 at-bats achieved mostly during his National League days.
Ichiro Suzuki, LF (.332, 12 HR, 56 RBI): Ichiro has racked up 278 hits in 837 Interleague at-bats with a .377 on-base percentage, which is a full career for a lot of players.
Miguel Olivo, C (.269, 19 HR, 64 RBI): Olivo will miss the Rockies series while on the DL, but should be back for the June games. He's put up pretty good numbers in 101 Interleague games in his career.
Last year: The Mariners went 9-9 in Interleague Play when they faced the NL East. They got swept in three-game sets by the Braves and Nationals and went 2-1 against the Phillies and Marlins. The saving grace was a 5-1 record against the Padres, their "natural rivals" from the NL West.
All-time: Seattle has the sixth-best Interleague record among all Major League teams at 145-121 (.545 percent). The Mariners have posted a .500 or better record for the past 12 years, which is the second-longest run of any MLB team behind only the Yankees' 14. Since 2000, they've gone 124-92 (.574).
at Rockies, May 18-20:Buy tickets The Mariners make their first trip to Coors Field since 2009, when they got swept in three games. They're 13-12 all-time vs. Colorado, but 4-7 in Denver. The Mariners aren't going to face Jamie Moyer, but they will get to see plenty of standout shortstop Troy Tulowitzki and outfielder Carlos Gonzalez.
vs. Dodgers, June 8-10:Buy tickets The Dodgers visit Safeco Field for just the second time, having last played in Seattle in 2000 after twice coming to the Kingdome in the late '90s. The Mariners lead the series 12-10, including 5-3 in Seattle. It's a great chance for Seattle fans to see star outfielders Matt Kemp and Andre Ethier and maybe pitcher Clayton Kershaw if the rotation falls right.
vs. Padres, June 12-14:Buy tickets Seattle is 25-11 against San Diego over the past six years and 44-36 all-time. The Mariners won 5 of 6 last year. This will be first chance for Safeco fans to see promising young first baseman Yonder Alonso, acquired from the Reds last offseason. The two teams meet again at Petco Park on June 22-24.
vs. Giants, June 15-17:Buy tickets The Mariners are 9-5 against San Francisco in Seattle, including 7-2 at Safeco Field, and 12-10 overall. Mariners fans can hope the pitching matchups line up for a homecoming appearance for pitcher Tim Lincecum, while they'll definitely get a chance to see young catching standout Buster Posey in action.
at Diamondbacks, June 18-20:Buy tickets Seattle makes its first trip to Chase Field since a series sweep in '06. The Mariners are 6-3 in Phoenix and 12-5 overall against the D-backs. A couple of former Mariners, infielder Willie Bloomquist and closer J.J. Putz, play key roles for the defending NL West champs.