Background: Recent studies suggest that patients undergoing Roux-en-Y gastric bypass (RYGB) for morbid obesity are at risk for hyperoxaluria, nephrolithiasis, and oxalate nephropathy. Our objective was to conduct a long-term prospective longitudinal study to establish the incidence, clinical progression, and severity of hyperoxaluria after RYGB. Study Design: Patients undergoing RYGB between December 2005 and April 2007 provided 24-hour urine collections for comprehensive stone risk analysis 1 week before and 3 months and 1 and 2 years after surgery. Primary outcomes were changes in 24-hour urinary oxalate excretion and relative supersaturation of calcium oxalate from baseline to 2 years post-RYGB. Results: The cohort consisted of 21 patients, including 5 (24%) men and 16 (76%) women. Mean preoperative age and body mass index (calculated as kg/m2) were 48.2 ± 10.5 years (range 25 to 64 years) and 50.5 ± 9.1 (range 39.7 to 66.6), respectively. Urinary oxalate excretion increased significantly after RYGB (33 ± 9 mg/day versus 63 ± 29 mg/day; p ≤ 0.001). De novo hyperoxaluria developed in 11 (52%) patients. Increasing age at the time of surgery was predictive of de novo hyperoxaluria developing (odds ratio = 1.162; 95% CI, 1.002-1.347; p = 0.046). The percentage of patients with hypocitraturia increased from 10% at baseline to 48% at 2 years. The relative supersaturation of calcium oxalate was unchanged (1.73 ± 0.67 versus 2.20 ± 2.07; p = 0.27). Conclusions: RYGB is associated with a long-term increase in urinary oxalate excretion and decrease in urinary citrate excretion. Although calcium oxalate relative supersaturation increases early in the postoperative period, this returns to baseline with long-term follow-up. These data suggest that patients who have undergone RYGB are at risk for oxalate nephropathy developing.