Idiopathic uric acid nephrolithiasis is characterized by elevated urinary net acid excretion and insufficient buffering by ammonium, resulting in excessively acidic urine and titration of the relatively soluble urate anion to insoluble uric acid. Patients with type 2 diabetes have similar changes in urinary pH, net acid excretion and ammonium in 24 hour urine collections at baseline, even after controlling for dietary factors, and are at increased risk for uric acid nephrolithiasis. However, not all patients with type 2 diabetes develop kidney stones, suggesting that uric acid stone formers may have additional urinary defects, perhaps not apparent at baseline. We performed a metabolic study of 14 patients with idiopathic uric acid nephrolithiasis, 13 with type 2 diabetes, and 8 healthy control subjects of similar body mass index. Following equilibration on a fixed diet for 5 days, subjects were given a single oral acid load (50 mEq ammonium chloride), and urine was collected hourly for 4 hours. Uric acid stone formers had lower ammonium excretory response to acute acid loading compared with diabetic and non-diabetic non-stone formers, suggesting that an ammonium excretory defect unique to uric acid stone formers was unmasked by the acid challenge. The Zucker diabetic fatty rat also did not show impaired urinary ammonium excretion in response to acute acid challenge. Blunted renal ammonium excretory response to dietary acid loads may contribute to the pathogenesis of idiopathic uric acid nephrolithiasis.