Rookie right-hander Henry Sosa gets the first opportunity game series with the Chicago Cubs.
Houston dropped Friday's opener, 4-3, in 12 innings for its 99th loss of the season. The Astros have never lost 100 games in one year, dating back to their origins as the Colt 45s in 1962.
The franchise's highest loss total entering 2011 had been 97 - in 1965, 1975 and 1991. It lost 90 games or more in each of its first seven seasons, but had reached 90 just three times since.
No. 99 came Friday when Chicago's Marlon Byrd drove in the winning run with a dribbler down the third-base line in the bottom of the 12th.
David Carpenter (0-3) loaded the bases with one out in the 12th. Byrd's hit bounced off the third-base line and seemed to land in foul territory before Chris Johnson touched the ball with his glove. It was ruled a fair ball on the field, which allowed Starlin Castro to score the winning run.
Houston first baseman Carlos Lee went 3-for-5 with a pair of homers, including a game-tying two-run blast in the ninth.
Wandy Rodriguez allowed three runs on six hits over 5 2/3 innings for the Astros, who have lost two in a row.
Sosa, a 26-year-old Dominican, was signed as an undrafted free agent in 2004 and made his major-league debut on Aug. 10 with a six-inning outing in a 6-3 loss at Arizona.
He faced the Cubs and took a 4-3 loss in his second start five days later, then won two straight before dropping 3-1 and 8-2 verdicts in his last two outings against Washington and Pittsburgh.
Overall, in 37 2/3 innings, he's allowed 36 hits, 21 runs and 15 walks while striking out 28.
In the loss to the Cubs, also at Wrigley, he was touched for seven hits and four runs in six innings.
He's opposed by Mexican veteran Rodrigo Lopez, who got the win in the Aug. 15 matchup after lasting 5 1/3 innings and allowing three runs on five hits.
The 35-year-old, who's made 251 big-league appearances, is 2-2 in seven career meetings with the Astros - posting a 5.05 earned run average across 35 2/3 innings.
Lopez was a 12-8 winner at Cincinnati in his last start on Sept. 12, ending a four-start skid in which he'd gone 0-3 with a no-decision.
The Cubs are 5-5 in his last 10 appearances.