A number of adverse reactions have been associated with sulindac, a nonsteroidal anti-inflammatory drug, but acute hemolytic anemia associated with sulindac has not yet been reported, to our knowledge. We encountered two cases of severe immune hemolytic anemia, one fatal, which appear to have been related to sulindac. In vitro studies provided evidence that antibodies to sulindac and its metabolites were present in the serum of both patients.