On December 19, 2004, the Boston Red Sox signed Rentería to a four-year, $40 million contract with an option for 2009 to replace free agent Orlando Cabrera at shortstop. On April 14, 2005, he hit his first home run with the Red Sox off Randy Johnson of the Yankees. His double in the eighth inning of that game was the game winner in an 8–5 victory for Boston. From May 26 to 29, he had four straight games with at least three hits, the longest streak since George Brett had six (the record) in 1976. During that stretch, on May 28, 2005, he went three for three with a grand slam and five RBI in a 17–1 victory over the Yankees. The next day, he had four hits, including a home run, in a 7–2 victory over New York. For his efforts that week, he won his third career Player of the Week Award. He set a new career high for hits in a month when he had forty hits in August, second in the major leagues. He had a game-winning single on September 24, 2005 off B. J. Ryan of the Baltimore Orioles in a 4–3 victory. The win moved the Red Sox into a tie with the Yankees for the AL East lead. He scored one hundred runs in a season for the first time when he scored both runs in a 7–2 loss to Toronto on September 28. He finished the year with a .276 batting average and 172 hits. He struggled defensively, though, as he led the major leagues with a career-high 30 errors, and Red Sox fans soon began booing him after he only batted .228 in April. Renteria batted only .231 in the 2005 ALDS as the Red Sox would lose the division series to the Chicago White Sox in just three games. The Red Sox were also disappointed with his performance, and on December 8 he was traded to the Atlanta Braves for prospect Andy Marte.