Anti-M is usually a naturally occurring antibody directed against M in the MNS blood group system. It does not require exposure to the antigen from previous transfusion or pregnancy. Anti-M is usually of the immunoglobulin M (IgM) isotype, binds best at about 4°C, binds well at room temperature, and rarely binds at 37°C. As a result of its lack of binding at 37°C, anti-M is usually clinically insignificant. There have been rare cases reported of an anti-M that reacts at 37°C. Such an exceptional anti-M may cause hemolytic transfusion reactions. We report a case of a warm-reactive anti-M and the investigational process used to identify it.