Natural killer (NK) activity was assessed in a prospective fashion in 15 renal transplant recipients receiving single HLA-haplotype matched allografts and maintained on cyclosporine (CYA) immunosuppression. There was marked variability in NK activity pretransplantation in this population; however, a strong correlation (r = 0.92, p less than 0.01) was found between determinations in an individual patient upon repeated testing. No significant depression of NK activity occurred within the first 12 weeks following transplantation. Whole blood CYA levels did not correlate with NK activity. Although NK activity prior to transplantation did not predict clinical outcome of the allograft, a marked rise in NK activity was observed in patients undergoing rejection compared with those not rejecting (p less than 0.01). A large increment in activity was seen in eight of 11 rejection episodes; a similar increase was rarely seen in the absence of rejection. These results indicate that NK activity is stimulated during allograft rejection in CYA treated renal transplant recipients. It remains to be determined whether this rise in NK function represents a manifestation of alloreactivity accompanying the rejection process or whether NK cells directly contribute to allograft destruction.