Between 1975 and 1983, 838 patients were randomized into the Program on the Surgical Control of Hyperlipidemias (POSCH) trial: 417 to standard medical care and 421 to partial ileal bypass (PIB) surgery. During the course of the trial, an increased incidence of kidney stone formation was found in the surgery group (4%/year) as compared to the control group (0.4%/year). A matched triplet case-control study was conducted to assess the possible causes for the increased incidence of kidney stones. Three groups were studied: PIB stone-formers (S); PIB non-stone formers (N); and non-PIB, non-stone formers in the control group (C). Initially, 162 patients (54 triplets) were selected. Ten percent of the patients declined to participate which resulted in a sample size of 146 patients. The PIB patients had statistically significant (P less than 0.05) lower levels of serum vitamin D metabolites; lower urine volume, pH, citrate, magnesium, carbon dioxide, and sulfate, and higher urinary oxalate, ammonia and relative supersaturation for calcium oxalate and uric acid than the control patients. Although S and N had similar results, those S with no prior history of stones had a higher calcium oxalate supersaturation than similar N with a negative prior history of stones (P less than 0.025). Based on these results, all PIB patients appear to be at risk for kidney stone formation. The combination of reduced urinary volume and calcium oxalate precipitation inhibitor substance with increased calcium oxalate relative supersaturation produced an increase in nephrolithiasis risk in the PIB groups.