The influence of cyclosporine (CsA) on secondary and established alloantibody responses was evaluated in inbred Lewis rats and (AO x PVG)F1 hybrid rats. Lewis rats received weekly transfusions of DA whole blood for 8 weeks either with or without cyclosporine (15 mg/kg/day) after sensitization with DA splenocytes. Hybrid rats received only CsA (10 mg/kg/day) after similar sensitization. Administration of CsA did not affect the spontaneous decline in alloantibody titers against class I (RT1A) antigens, but it was associated with a significantly reduced response to class II (RT1B) antigens at the end of the study. CsA prevented maintenance of high alloantibody titers to RT1A antigens in Lewis rats transfused repeatedly following sensitization. IgG alloantibody subclass responses were also altered by CsA with significant reduction in titers of IgG1, 2a, and 2b against RT1A antigens in rats transfused repeatedly; CsA did not, however, suppress IgG2c alloantibody levels in these animals. Responses to public RT1A antigens disappeared in most animals irrespective of their treatment group, whereas those to private and public RT1B antigens persisted unless CsA was administered. The results suggest that, contrary to results obtained with other antigens, CsA does influence secondary alloantibody responses. CsA may thus prove of value in highly sensitized dialysis patients who require further blood transfusions.