Purpose We tested the hypothesis that the cationic phosphate binder sevelamer hydrochloride could reduce hyperoxaluria and calcium oxalate supersaturation in patients with enteric hyperoxaluria by binding fatty acids, binding phosphate and rendering calcium free to bind oxalate, and/or directly binding oxalate. A secondary objective was to assess changes in the urinary excretion of other substances associated with nephrolithiasis. Materials and Methods Ten patients with enteric hyperoxaluria were enrolled in a nonrandomized, open label trial of sevelamer hydrochloride (3,200 mg 3 times daily for 7 days). Results With treatment mean urinary oxalate decreased 17% (0.84 to 0.70 mmol per day) and the urinary oxalate-to-creatinine ratio decreased 11% (0.055 to 0.049 mmol/mmol, p not significant for both). Urinary calcium increased 25% (p not significant). Urinary citrate decreased 23% (p = 0.01) and urinary phosphorus decreased 44% (p = 0.0001). Mean supersaturation of calcium oxalate, brushite, hydroxyapatite, uric acid and sodium urate did not change significantly. However, the decrease in brushite supersaturation approached statistical significance (p = 0.07). Mean serum phosphorus was 3.6 mg/dl at baseline and 3.3 mg/dl with therapy (p not significant). Hypophosphatemia did not develop in any patients. One patient dropped out of study due to abdominal pain. Conclusions Sevelamer hydrochloride dramatically decreased urinary phosphorus excretion with a lesser effect on urinary oxalate. Supersaturation of calcium oxalate did not decrease due to countervailing effects on other constituents including an increase in urinary calcium and a decrease in urinary citrate. Although sevelamer hydrochloride may not be an ideal agent for correcting hyperoxaluria, its potential to reduce calcium phosphate supersaturation merits further investigation.