The current study is an examination of the magnitude of the home advantage during interleague play in Major League Baseball. Interleague play provides a unique opportunity to assess the impact of a rule factor, the Designated Hitter (DH), and a learning factor, facility familiarity. Secondary data was used to analyze the home advantage during interleague play in Major League Baseball. Win-loss records, team statistics (e.g., team errors), and player statistics (number of Hits and Runs Batted In (RBIs) for designated hitters and pitchers were collected from Major League Baseball`s archives (www.mlbreference.com), Data was collected beginning with the 1997 season, the year interleague play began, through the 2007 season. Three hypotheses were tested. The results indicated during interleague play both the American and National League teams had higher home winning percentages than their respective away winning percentages. There were, however, no significant differences between the home winning percentages during interleague play compared to regular season play. The results further indicated that the National League teams committed fewer errors, both home and away, during interleague play compared to the American League teams. Finally, the batting performance of the American League team`s designated hitters (hits, batting average, RBI, and bases on balls) was higher than the batting performance by the National league team`s designated hitters.