Evaluation of a CF population gave preliminary indications that all pancreatic insufficient (PI) patients were at elevated risk for stones, whether or not they had a prior history of stone formation. The prevalence of stone formation in our CF population (147 pt ≥ 18 yr.) was 7.5%. However, 7 of 11 pts with stones had prior onset of diabetes mellitus. The occurrence of nephrolithiasis was 27% in the CF/DM population and 3% in the CF/non-DM controls. CF patients and non-stone forming (non-SF) control patients were evaluated for factors contributing to the occurrence of kidney stones. Significantly abnormal values (mean +/- SEM) observed included: low urine volume (1.63 ± 0.9 L/day SF & 1.59 ± 0.5 L/day non-SF); low urinary citrate (189.6 ± 119 mg/day SF & 228.8 ± 112 mg/day non-SF); increased relative supersaturation for calcium oxalate (2.8 ± 1.0 SF & 2.4 ± 0.8 non-SF); calcium phosphate (4.6 ± 2.5 SF); sodium urate (3.4 ± 2.1 SF & 2.4 ± 1.2 non-SF) and uric acid (2.7 ± 2.1 non-SF). Correlation to the risk profile of significantly decreased values of urine output, saturated calcium oxalate and citrate was confirmed by chemical analysis of 3/3 recovered stones which revealed mostly calcium oxalate. Reoccurrence (21 events in 11 SF patients) underscores the need for specific assessment of individual risk parameters prior to medical intervention. These results strongly indicate that as the CF population ages, there is an increasing and measurable risk for calcium oxalate nephrolithiasis and that the CF/DM subpopulation has an order of magnitude increased risk.