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Systemic immunosuppression frequently results in severe side effects. To evaluate a method of limiting the adverse effects of immunosuppression, we implanted controlled release matrices containing cyclosporine-A (Cy) embedded (0.2 or 1 mg/kg/day released), steroid embedded (2%, 0.2% and 0.02% dexamethasone, Dex) or both (Cy 0.2 mg and Dex 0.2%) locally around the transplanted heart at the time of rat heterotopic (neck) heart transplants. Controls received empty (non-drug) matrix implants. To elucidate a local effect, additional groups received Cy (0.2 mg) or Dex (0.2%) matrix implanted in a subdermal distal leg pouch at the time of heart transplant, without a local neck implant. Rejection was determined by the lack of transplanted heart contractions. Recipient animals received no other form of immunosuppression. The Cy (0.2 mg) animals had whole-blood Cy levels monitored for 6 weeks following transplantation. Cy levels peaked at 7-10 days after transplant (119 ± 26 ng/ml) and decayed to <50 ng/ml by day 42. At no time did whole-blood Cy levels reach clinically significant levels. Additional animals had whole-blood, heart and kidney Cy levels measured at day 6 post-transplant. Both doses of local Cy demonstrated good survival benefit and were well absorbed locally, resulting in high Cy levels in heart tissue (>9,000 ng/mg). Furthermore, while low-dose Cy (0.2 mg) demonstrated significant survival benefit, these animals had clinically negligible blood Cy levels on day 6 (<100 ng/ml) and very low kidney Cy levels. Interestingly, the lowest dose of Dex demonstrated no survival benefit, while the mid- and high-Dex doses demonstrated good survival benefit: however, the high-Dex dose had poor wound healing. Cy and Dex combination did not increase efficacy, perhaps due to release problems from physicochemical interactions. Local immunosuppression with a controlled release matrix resulted in a significant survival advantage and was effective in delaying rejection. This appro