We have attempted to determine the optimal clinical use of cyclosporine during the first 3 months after heart transplantation. We used multiple logistic regression to quantify how blood cyclosporine concentrations and other potential risk factors influence the risk of histologically confirmed acute rejection in 111 heart transplant recipients. A 50% increase in cyclosporine concentration was associated with a 15% reduction in risk of rejection in the subsequent 5 days (P=0.002). Increasing oral corticosteroid dose also protected against rejection (P=0.01). Rejection was over 2.5 times more likely during the first 20 postoperative days, and patients with 2 HLA-DR mismatches who were transplanted for cardiomyopathy or who had multiple previous rejection episodes were predisposed to further rejection (P<0.01). High short-term variability in cyclosporine concentrations was weakly associated with risk of rejection (P=0.1). Investigation of threshold levels for the cyclosporine concentration-effect relationship suggested that concentrations above 375 microgram L(-1) provide optimal protection against acute cardiac allograft rejection. This result yields an objectively defined therapeutic threshold for targeting early cyclosporine concentrations following heart transplantation, although the upper end of the range will depend on the individual's susceptibility to nephrotoxicity and infection.