Renomedullary interstitial cell tumors are common incidental findings in kidney specimens. Despite their frequency, little is known about their morphology and pathogenesis. Kidneys from 402 unselected autopsies were sectioned at 1 to 2 mm intervals, and all lesions were examined histologically. A total of 421 renomedullary interstitial cell tumors were present in 150 patients (37%), ranging from 1 to 23 tumors per patient (mean=3). There was no statistically significant difference in age, sex, hypertension, heart weight, tobacco smoking, diabetes mellitus, and renal function between patients with renomedullary interstitial cell tumors and those without. Almost half the patients with renomedullary interstitial cell tumors (41%) had bilateral tumors, and they were older than patients with unilateral tumors (P=0.0007). The tumors ranged in size from 0.5 to 6 mm (mean 1.7 mm). The lesions varied in cellularity: fibrous stroma was found in older patients, whereas cellular and hypocellular stroma predominated in younger patients (P=0.001 and P<0.0001, respectively). Entrapped renal tubules were found throughout the tumor in younger patients and smaller tumors, whereas the absence of entrapped tubules or their location only at the periphery of the lesion were common in older patients and larger tumors (P=0.02 and P<0.0001, respectively). Ropey brightly eosinophilic material, found in 26% of tumors, was not amyloid but collagen type III. This material was observed in older patients (P<0.0001) with larger tumors (P<0.0001) and was also correlated to higher heart weight (P=0.003) but not to hypertension (P=0.11). On the basis of our findings, renomedullary interstitial cell tumors appear to originate as a proliferation of renomedullary interstitial cells between medullary tubules. As their size increases, cellularity decreases, ropey eosinophilic material is deposited, and tubules disappear.