Liver transplant patients were enrolled in a study designed to investigate correlations between plasma complement C3a or C4a levels and various postoperative complications. Longitudinal EDTA-plasma levels of C3a and C4a were measured by quantitative radioimmunoassay. Acute rejection gave a characteristic and marked increase in blood C3a, C4a and gamma-glutamyl transferase (gammaGT) levels, which rapidly resolved after high dose steroid treatment. Cytomegalovirus (CMV) infections in two of three patients gave an initial small increase only in C3a levels (i.e., alternative pathway activation) followed approximately 6 weeks later by a marked increase in C4a levels (i.e., classical or lectin pathway activation). In a third patient diagnosed for CMV infection, the complement activation profile was complicated by a coincident minor rejection episode. However, a late stage elevation in C4a was also noted. Two patients experiencing biopsy proven recurrent hepatitis C infections following transplantation exhibited increases in both gammaGT and C4a levels, without a significant increase in the level of C3a. Several hepatitis C and one hepatitis B patient had multiple late activation episodes involving marked elevation in both plasma C3a and C4a levels without detectable increases in the liver enzymes conventionally used to monitor organ function. We also showed that ex vivo activation of complement in EDTA plasma from all transplant patients was abnormally high. The classical or lectin pathway is believed to be responsible for this excessive ex vivo complement activation in the plasma of these patients. Therefore, subclinical rejection episodes and/or viral infections may be effectively detected or monitored by measuring C3a and C4a levels in plasma samples from liver transplant patients. Routine measurement of plasma complement products may provide an early non-invasive mode for detecting infections and also serve to monitor chronic or acute changes in the patient's immune system.