Activation mechanisms of B‐1 (Ly‐1 B) cells have been suggested to be different from those of conventional B cells. To assess the role of various interleukins (IL) in the activation of B‐1 cells, we injected IL‐4, IL‐5 or IL‐10 into nonanemic anti‐red blood cells (RBC) autoantibody‐transgenic mice, in which conventional B cells are clonally deleted but peritoneal B‐1 cells persist without secreting Ig. Intraperitoneal or intramuscular injection of IL‐5 or IL‐10, but not IL‐4, increased the number of antibody‐producing peritoneal B‐1 cells by four‐ to five‐fold, resulting in increased anti‐RBC serum autoantibody and induction of hemolytic anemia. These results suggest that IL‐5 or IL‐10 may play an important role in the terminal differentiation of B‐1 cells into antibody‐producing cells in vivo.