Twenty-three renal oncocytomas and 18 granular renal cell carcinomas (GRCC) were comparatively studied clinicopathologically and by DNA flow cytometry to delineate their differences. Of the patients with renal oncocytomas, 15 were men and 8 were women, and their ages ranged from 42 to 81 years (mean, 64 years). The gross appearance of renal oncocytomas was characteristically homogeneous tan-brown, with variable scarring, without areas of large hemorrhage, and with no apparent necrosis. Twenty-two renal oncocytomas were confined within the kidney (Robson stage I) and one tumor extended into the renal vein (stage IIIa). Twenty-two renal oncocytomas, including the stage IIIa tumor, manifested diploid DNA content and only one neoplasm showed a feature suggestive of near-diploid DNA aneuploidy. Of the 17 patients with renal oncocytomas who had adequate follow-up, none developed metastasis or died of disease. Of the patients with GRCC, 13 were men and 5 were women, and their ages ranged from 30 to 73 years (mean, 53 years). The gross appearance of GRCC was variegated, yellow to tan, and punctuated with geographic areas of necrosis. Eleven patients with GRCC were stage I, 4 were stage II, 2 were stage IIIa, and 1 patient had metastases at initial examination (stage IV). Seven GRCCs were DNA diploid, one was DNA tetraploid, and 10 tumors were DNA aneuploid. Twelve patients were alive with no evidence of disease (12 to 36 months; median, 26 months). All patients with DNA diploid neoplasm pursued benign clinical courses. One patient was alive with metastatic disease and two patients developed metastases and died of their disease; all three patients had DNA aneuploid tumors. Two patients died of other causes and one patient was lost to follow-up. Our data indicate that renal oncocytoma is a distinct clinicopathologic disease with characteristic gross, histologic, DNA flow cytometric, and biologic features that are different from GRCC.