Markakis began his first spring training with the Orioles in 2006 by reaching base in nine of his first ten plate appearances. He earned an Opening Day roster spot. Markakis made his major league debut on April 3, 2006, when he was used as a late-inning defensive replacement against the Tampa Bay Devil Rays. He received his first start and plate appearances two days later. Hitting second and playing left field, he drew three walks in his first three plate appearances and hit a 400-foot home run for his first major league hit in the 16–6 win.