H-l1 (Ag-B1-histocompatible rats were cross-immunized to study the effects of presensitization on the mixed lymphocyte culture (MLC) reactivity in normally nonresponsive MLC interactions. Lewis (LEW) rats, H-l1 (Ag-B1), were given s.c. injections of Fischer (F), H-l1 (Ag-B1), lymphocytes at weekly intervals for 3 weeks. Immunized LEW (Lew-iF) and F lymphocytes showed increased proliferative responses in MLC after the third immunization. The augmented proliferative responses in the MLC between these H-l1 (Ag-B1)-histocompatible rat strains following immunization may reflect minor histocompat-ibility antigenic differences. On the other hand, decreased proliferative responses in MLC between Lew-iF and Ag-B (H-1)-disparate rat strains were demonstrated. Alloimmunization across minor histocompatibility differences led to different types of regulatory effects on the MLC interactions. With low MLC responses, e.g., minor histocompatibility differences, the regulation tends to be positive; whereas for strong MLC responses, e.g., major H-l (Ag-B) differences, the regulation tends to be negative or suppression.