Balance studies and oxalate loading tests were carried out in order to define the pathogenesis of hyperoxaluria in 8 patients with jejunoileal bypass surgery for severe obesity; two healthy volunteers were also studied. In the bypass patients, urinary oxalate was markedly elevated (118 +/- 43 mg/day, mean +/- SD) when they were on a high oxalate diet (252 mg/day). Hyperabsorption of dietary oxalate was confirmed by the markedly increased urinary recovery of [14C]oxalate given in a test meal. In addition, the oxalate radioactivity was excreted in urine far more slowly than in healthy volunteers, suggesting that the colon was a major site of oxalate absorption. Elevated urinary oxalate excretion persisted, averaging 38 +/- 12 mg/day, despite ingestion of a very low oxalate diet (approximately 6 mg/day), suggesting that the diet contained "oxalogenic" substances other than preformed dietary oxalate which also contributed to dietary oxalate in these patients. Urinary oxalate decreased in 7 of 8 patients, however, when protein-rich foods were removed from the diet, suggesting that at least one dietary factor was digestive products of protein or creatinine. These results confirm the current view that in patients with hyperoxaluria secondary to jejunoileal bypass, the majority of urinary oxalate derives from dietary oxalate that is absorbed from the colon. Tissue or bacterial production of oxalate or an oxalate precursor from dietary constituents associated with protein, however, also appears to contribute to urinary oxalate. The results provide an explanation for the reported difficulty of eliminating secondary hyperoxaluria by restriction of dietary oxalate alone.