A method is described for distinguishing between graft rejection and cyclosporin nephrotoxicity in renal allograft recipients by analyzing fresh morning urine samples. The technique combines classic Papanicolaou with immunocytochemical staining and was performed in urine specimens from a series of 42 patients. Early-stage cyclosporin toxicity was usually associated with increased numbers of proximal tubular cells only, whereas in rejection and late-stage toxicity there were increases in both tubular cells and in lymphocytes and monocytes (greater than 2000 cells/ml urine). Differentiation between these two clinical conditions was achieved by immunostaining, which revealed that increased numbers of CD25+ and CD8+ cells, as well as an increase in the HLA-DR/Lu5 ratio, were typical of rejection. CD25 positivity proved to be the best indicator of rejection, with a sensitivity and specificity of more than 90%. A cytodiagnostic algorithm is presented that is based on cell numbers and types, including immunophenotypes. The proposed method has the advantage of being noninvasive and appears to represent a reliable and rapid adjunct for the monitoring of graft function, especially in high-risk patients on cyclosporin immunosuppression.