Cyclosporin A (Cy A) by itself is limited in its clinical application by its dose-related liver and kidney toxicity. Combining Cy A with prednisone allows lower doses of Cy A to be used, but the side effects of steroids are cumulative. The effect of Cy A and various drug-dose combinations with azathioprine (AZA) in 4 different rat and dog models. The one that gave the best results with the least toxicity was 1.25 mg Cy A plus 15 mg AZA for islet allotransplantation in rats across a minor histocompatibility barrier and for heterotopic heart allotransplantation in rats across a major histocompatibility barrier. In the latter, using the same strain of rats, no significant effect can be shown in rat pancreas allotransplantation. In canine renal allografts, only 1 dose combination (5 mg Cy A plus 2.5 mg AZA) was tested, but it was synergistic. Cy A may potentiate the myelosuppressive effect of AZA, and the dose may have to be adjusted to avoid this problem.