A microcytotoxicity assay was used to search for cell-mediated cytotoxicity, serum-blocking factors, and antibody-dependent cell-mediated cytotoxicity (ADCC) against fibroblasts of donor origin in 19 human renal allograft recipients. Peripheral mononuclear cells (PMC) were frequently cytotoxic when they were obtained within 6 days prior to rejection, following sustained rejections, and within 1 month after removal of rejected grafts, but the toxicity was usually nonspecific. Recipient PMC were noncytotoxic when they were obtained within 6 days after the onset of an acute reversed rejection and during quiescent intervals when there was no evidence of rejection within 6 days before or after the assay. These data suggest that, regardless of its lack of specificity, there is some relationship between cytotoxicity of recipient PMC and allograft rejection. In none of 69 post-transplant serum samples was ADCC against donor target cells detected with the microcytotoxicity assay.