The 2006 Major League Baseball All-Star Game was the 77th playing of the midseason exhibition baseball game between the all-stars of the American League (AL) and National League (NL), the two leagues comprising Major League Baseball. The game was held on July 11, 2006 at PNC Park in Pittsburgh, Pennsylvania, the home of the Pittsburgh Pirates of the National League. The contest was the fifth hosted by the city of Pittsburgh – tying the Cleveland Indians for the record of most times hosted by a single franchise. The game resulted in the American League defeating the National League 3–2, thus awarding the AL champion (which was eventually the Detroit Tigers) home-field advantage in the 2006 World Series.

As with each All-Star Game since 1970, the 8 starting position players (with no designated hitter due to playing in an NL stadium) of each league were elected by fan balloting. The remaining players were selected by a players' vote, each league's team manager, and the All-Star Final Vote to add one more player to each roster. In all, 32 players were selected to each league's team, not including players who decline to play due to injuries or personal reasons.

The game was the fourth straight All-Star Game to decide home-field advantage in the World Series. The AL entered the game on a nine-game unbeaten streak (eight wins, with one tie in 2002). Many analysts saw the disparity between the leagues as more pronounced than ever this season,^[1] as evidenced by the AL's dominance in interleague play, where its 154–98 record was the best for either league in the ten-year history of the format.^[2] This was primarily the result of a similar difference in team payrolls, many observers agreed. The AL boasted the four largest in the majors, while the NL had three of the four lowest among the 30 teams. At $194.7 million, the New York Yankees payroll was more than those of the Florida Marlins, Colorado Rockies, Pittsburgh Pirates and Milwaukee Brewers combined.

Players in italics have since been inducted into the National Baseball Hall of Fame.

The Century 21 Real Estate Home Run Derby was held on the Monday before the game, July 10. Four players from each league competed to hit as many home runs in each round to advance and eventually win the contest. This year's Derby featured an important rule change: home runs in the first round would carry over into the second round. In previous years, some players would hit a tremendous amount of home runs in the first round, but become tired by the second round and hit relatively fewer home runs for that round, often not enough to qualify for the finals. By allowing the home runs to carry over, a player can't necessarily be "punished" for hitting an impressive total in the first round. However, like in previous Derbies, the two finalists start over at zero for the finals.

In the finals, Ryan Howard of the Philadelphia Phillies defeated David Wright of the New York Mets 5–4, and hit a total of 23 home runs on the night, leading all competitors. Howard memorably hit his winning home run into a sign guaranteeing one person in the crowd 500 free round-trip flights from Southwest Airlines.^[6]

PNC Park is distinct for having the Allegheny River running behind the right field bleachers. As a result, several balls were hit into the river on the fly (a feat that had only been accomplished once before in the stadium's regular-season history), as well as many more bouncing off the walkway alongside the river. Many fans waited in the river in canoes hoping to retrieve a ball, a sight more reminiscent of the following year's All-Star Game and Home Run Derby site, AT&T Park.

For the second straight year, gold balls were utilized whenever a player had one out remaining in the round. Any home runs hit with the gold ball meant Major League Baseball and Century 21 would pledge to donate $21,000 (US) to the Boys & Girls Clubs of America and Easter Seals, respectively.^[7] In all, 14 gold-ball home runs were hit, constituting $294,000 raised for both charities.

• Penny became only the second pitcher in All-Star Game history to strike out the side in the first inning. Pedro Martínez accomplished the feat in 1999, striking out Barry Larkin, Larry Walker, and Sammy Sosa.
• At one point 7 of the 8 position players fans could vote on in the AL were either New York Yankees or Boston Red Sox.
• The 2006 Home Run Derby was the last year that Century 21 sponsored it, as the 2007 Home Run Derby was sponsored by State Farm.
• The Pirates became the first team to host the All-Star Game in three different stadiums. The others before PNC Park were Forbes Field and Three Rivers Stadium, both of which hosted the game twice.