Objectives To determine whether the biochemical presentation and urinary physicochemical environment of patients with hyperuricosuria presenting with calcium stones (hyperuricosuric calcium urolithiasis [HUCU]) differs from those of patients with gouty diathesis (GD) or idiopathic uric acid urolithiasis. Methods A total of 122 patients with HUCU and 68 patients with GD were identified from our “stone registry” of patients who underwent a full ambulatory evaluation. All patients with HUCU had urinary uric acid greater than 800 mg/day in men and greater than 750 mg/day in women and presented with calcium stones. Those with GD had pure uric acid stones or mixed uric acid-calcium stones and did not have secondary causes of uric acid urolithiasis. Data derived from the fasting serum and 24-hour urine samples collected on a random diet and on a diet restricted in calcium, sodium, and oxalate were compared between the two groups. Results Compared with patients with HUCU, those with GD had significantly higher serum uric acid and lower urinary uric acid and pH levels (mean value 5.38 and 5.35 on random and restricted diets versus 6.09 and 6.14, respectively). The fractional excretion of urate and the discriminant score of the relationship between urinary pH and the fractional excretion of urate were significantly lower in those with GD than in those with HUCU. Patients with HUCU displayed a greater urinary saturation of sodium urate and calcium oxalate compared with those with GD, and those with GD had a higher urinary content of undissociated uric acid and lower urinary saturation of brushite (calcium phosphate). Conclusions Patients with HUCU presented with normal urinary pH and hyperuricosuria, accompanied sometimes by hypercalciuria, which produced increased urinary saturation of sodium urate and calcium oxalate. In contrast, those with GD had a low fractional excretion of urate (that contributed to hyperuricemia) and low urinary pH (that led to increased amount of undissociated uric acid). The varying biochemical and physicochemical presentations of the two conditions can be ascribed to overindulgence with purine-rich foods in those with HUCU and underlying primary gout in those with GD.