After missing the 2010 season (save for a brief stint in the Cincinnati Reds organization), in February 2011, Isringhausen returned to the Mets, signing a minor league deal with the team. After spending time in the minors, Isringhausen performed well in his return to the Majors with the Mets and eventually landed the job of setup man for Mets closer Francisco Rodriguez. After Rodriguez was traded to the Milwaukee Brewers in the middle of the season, Isringhausen was slotted into the closer role and eventually earned his 300th save against the San Diego Padres.