Rats with small bowel resection fed a high-oxalate diet develop extensive deposition of calcium oxalate (CaOx) and calcium phosphate crystals in the kidney after 4 mo. To explore the earliest sites of renal crystal deposition, rats received either small bowel resection or transection and were then fed either standard chow or a high-oxalate diet; perfusion-fixed renal tissue from five rats in each group was examined by light microscopy at 2, 4, 8, and 12 wk. Rats fed the high-oxalate diet developed birefringent microcrystals at the brush border of proximal tubule cells, with or without cell damage; the lesion was most common in rats with both resection and a high-oxalate diet (10/19 with the lesion) and was significantly correlated with urine oxalate excretion (P < 0.001). Rats with bowel resection fed normal chow had mild hyperoxaluria but high urine CaOx supersaturation; four of these rats developed birefringent crystal deposition with tubule plugging in inner medullary collecting ducts (IMCD). Two rats fed a high-oxalate diet also developed this lesion, which was correlated with CaOx supersaturation, but not oxalate excretion. Tissue was examined under oil immersion, and tiny birefringent crystals were noted on the apical surface of IMCD cells only in animals with IMCD crystal plugging. In one animal, IMCD crystals were both birefringent and nonbirefringent, suggesting a mix of CaOx and calcium phosphate. Overall, these animals demonstrate two distinct sites and mechanisms of renal crystal deposition and may help elucidate renal lesions seen in humans with enteric hyperoxaluria and stones.