There are no accurate noninvasive methods to distinguish renal allograft dysfunction due to rejection or cyclosporine nephrotoxicity. We have studied the value of Tc-99M-DTPA renal scanning in 90 episodes of renal allograft dysfunction occurring in 44 patients subjected to 57 renal biopsies in whom a clear diagnosis could be established. Renal scintigrams were assessed qualitatively and quantitatively by a blinded observer. Rejection was diagnosed when deterioration in perfusion occurred in the presence of maintained or declining radionuclide excretion. The diagnosis of cyclosporine nephrotoxicity was made by exclusion. The final diagnosis was based on the clinical response to therapy and/or the findings on renal biopsy. The scintigraphic diagnosis of rejection had a specificity of 87.9% and significantly contributed to the exclusion of cyclosporine nephrotoxicity (negative predictive value of 90.6%). Furthermore, a scintigraphic diagnosis compatible with cyclosporine nephrotoxicity, in the presence of a drug level above the therapeutic range, indicated a 90.4% probability of true nephrotoxicity. We conclude that, even in cyclosporine-treated renal transplant patients, Tc-99M-DTPA scintigraphy is of clinical value and can be incorporated into an effective diagnostic algorithm for allograft dysfunction.