Previous studies in miniature swine have suggested that the mechanism underlying the spontaneous development of tolerance in one third of one-haplotype class I disparate renal allografts (ie, ag→ ad) involves a relative T cell help deficit at the time of first exposure to antigen. If this hypothesis were correct, then one might expect the administration of an immunosuppressive agent capable of inhibiting lymphokine production during this period to lead to the induction of tolerance to class I MHC antigens in two-haplotype class I mismatched renal allografts (ie, gg→ dd), which are otherwise uniformly and acutely rejected. This hypothesis was tested in eight two-haplotype class I disparate, class II matched donor-recipient pairs, in which recipients were treated with cyclosporine 10 mg/kg, ivqd for 12 days. This protocol led to the induction of long-term (> 100 days) specific tolerance in 100% of recipients, as compared with control animals that rejected grafts in 13.7±0.9 days (P< 0.0001). The specificity of tolerance was assessed both in vivo