Renal stone formation and renal failure among Chinese infants administered melamine-containing formula were increasingly reported in 2008. We investigated the mechanism by which melamine and cyanuric acid induce renal stone formation and renal failure. Ten-week-old rats were administered either melamine [2.4, 24, or 240 mg/kg/day], both melamine and cyanuric acid [each at 1.2, 12, or 120 mg/kg/day], or water (controls). Blood and 24-h urine samples and kidney sections were evaluated on days 3, 7, and 14. In rats administered melamine alone or the low-dose melamine/cyanuric acid combination [1.2 mg/kg/day], crystals were not detected. On day 3, crystal formation was observed in the renal distal tubular lumens and collecting ducts of rats administered the intermediate-dose melamine/cyanuric acid [12 mg/kg/day], and the number of crystals increased during the course of the experiment. In rats administered the high-dose melamine/cyanuric acid [120 mg/kg/day], crystals were found in the proximal tubular lumens of the renal cortex on day 3, but acute renal failure resulted in death by day 7. Polarized light optical microphotography and scanning electron microscopy revealed tubular lumens occluded by a layer of axle-shaped crystals. X-ray diffraction findings revealed a nitrogen component but no calcium. The upper regions of occluded tubes were expanded, and the epithelium was thin. Melamine and cyanuric acid in combination, but not by melamine alone induce crystal formation and affected renal functioning. Renal failure due to melamine cyanurate crystals appears to occur via tubular occlusion.