Antibody-dependent cell-mediated cytotoxicity (ADCMC) was studied retrospectively in 20 long-term (1.3-11 years) renal allograft recipients. The serum of all seven patients having persistent proteinuria greater than 1 g/24 hr exhibited positive ADCMC activity to donor lymphocytes. All 11 patients having a negative ADCMC test had normal levels of urinary protein (mean + 0.28 +/- 0.06 (SE) g/24 hr). Two patients had a positive ADCMC test but had normal urinary proteins and no evidence of chronic rejection. In the ADCMC positive group, the mean serum creatinine values were significantly higher and the mean creatinine clearance values were significantly lower than in the ADCMC negative group. There was no significant positive correlation between the presence of ADCMC and the number of HL-A mismatches identified or the response to donor lymphocytes in mixed lymphocyte culture tests in the two groups. Two patients had transplant nephrectomy and histologically showed both glomerular and arterial lesions of chronic rejection. Post-transplant ADCMC activity showed a significant correlation with proteinuria, decreased creatinine clearance, and elevated serum creatinine, and suggests that the chronic rejection syndrome may be related to ADCMC activity in the recipient.