Heterologous antilymphocytes sera (ALS) produced in several species against a variety of guinea pig lymphocytes populations were studied by immunoprecipitation experiments and polyacrylamide gel electrophoretic analyses to characterize the membrane proteins recognized by these antisera. Although a number of different proteins were recognized by these sera, high-titered antibodies against guinea pig Ia antigens could be demonstrated in all ALS, including those produced against thymocytes. Furthermore, selective absorptions and sequential precipitation experiments revealed significant levels of xenoantibodies that recognized specific Ia alloantigenic determinants. The potential significance of antibodies against Ia antigens in heterologous antilymphocyte and antithymocyte sera is discussed.