Reynolds made the Opening Day start in 2000, which made him the third Astro to have made five Opening Day starts (J.R. Richard and Mike Scott). Facing against Pittsburgh at the last Opening Day game held at Three Rivers Stadium, he went seven innings and allowed two runs on six hits while striking out four in a win as the Astros prevailed 5-2. He got onto a 5-0 start (with four no-decisions) before losing his first game on May 27. Leading into the MLB All-Star Game, he was on a downturn, as he was 6-5 in 18 games before his All-Star selection (his first and only in his career). He pitched just four games after that for the season.