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Background As significantly more patients die of infection than of rejection after liver transplantation, we have to conclude that overimmunosuppression is common. Our analysis was performed to investigate underlying disease as an appropriate parameter for individually reduced immunosuppression. Design A consecutive series of patients receiving primary liver transplantation was analyzed with regard to acute rejection. Setting Department of transplantation surgery in a university hospital. Patients and Methods From 1988 to 1995, 252 patients received liver transplantation for posthepatitic cirrhosis, alcoholic cirrhosis, cholestatic disease, or hepatoma and were analyzed in a univariate and multivariate manner. Main Outcome Measure The influence of various underlying diseases on the incidence of acute rejection. Results The estimated risk for freedom from acute rejection and analysis of cumulative rates of acute rejection stratified by group showed significant differences between the groups, except for alcoholic and posthepatitic cirrhosis. Severity of acute rejection episodes, as assessed by the need for rescue therapy, was similar in both univariate analysis and cumulative rates for alcoholic and posthepatitic cirrhosis. As expected, patients with cholestatic disease exhibited a significantly increased requirement for rescue therapy. For patients with hepatoma, a low incidence of initial and a high rate of repeated rescue therapy were observed. The varying immunological behavior within this group may have influenced both expansion of the tumor and severity of acute rejection. Multivariate analysis of potential risk factors identified underlying disease as a variable of independent prognostic significance for acute rejection and the need to receive rescue therapy. Conclusion These results indicate the importance of taking the original disease into consideration where immunosuppressive therapy is concerned.