Despite reduced risk of acute rejection and increased 1-year graft survival with modern immunosuppressive regimens, chronic allograft nephropathy and death with a functioning graft remain major causes of allograft loss beyond the first year post-transplant. Anti-rejection agents may influence renal transplant outcome not solely through their immunosuppressive activity but also through their effects on other prognostic risk factors. We have analysed 6-year follow-up data from 232 renal transplant recipients randomized to treatment with tacrolimus or cyclosporin microemulsion at the University Hospital of Wales, Cardiff. Tacrolimus-based therapy was associated with a more favourable cardiovascular risk profile than therapy with cyclosporin microemulsion, with an improved lipid profile, lower arterial blood pressure and lower homocysteine levels. Renal function at 1-year post-transplant is probably the most significant factor influencing long-term graft survival. In our analyses, renal function determined by the glomerular filtration rate was significantly better in tacrolimus-treated patients from month 3 post-transplant. Moreover, normal renal function was maintained throughout a 5-year follow-up in a significantly higher proportion of non-rejecting patients treated with tacrolimus than with cyclosporin microemulsion (58 versus 10%, respectively, at 5 years; P=0.002). Morphometric analysis of protocol biopsies revealed that the degree of interstitial fibrosis, similar in both treatment groups at baseline, was significantly greater in the cyclosporin microemulsion group over 12 months. Importantly, patients receiving tacrolimus had significantly greater 6-year graft survival (81 versus 60%, P=0.0496) and a higher projected graft half-life (15 versus 10 years) than those receiving cyclosporin microemulsion. Tacrolimus treatment is associated with a significantly better cardiovascular risk profile and superior renal function compared with cyclosporin microemulsion treatment, which appears to translate into improved long-term graft survival.