The present study was designed to evaluate the role of fluoride in urolithiasis in humans. Two areas were selected for this purpose, a fluoride endemic area (EA) and a fluoride non-endemic area (NEA). The prevalence of uroliathiasis was 4.6 times higher in EA than in NEA. Furthermore, the prevalence was almost double in subjects with fluorosis than without fluorosis in the endemic area. No relationship was observed between urolithiasis and the duration of fluorosis. The fluoride levels in drinking water ranged from 3.5 to 4.9 ppm in EA and subjects from this area excreted more fluoride. A comparison of normal subjects (NS) from EA and NEA revealed that endemic subjects tend to have slightly higher mean serum thiobarbituric acid reactive substance (TBAR) levels and excrete more oxalate and fluoride than their non-endemic counterparts. The urinary stone formers (SF) from the two areas showed a similar tendency, though again the difference was not significant. Citrate excretion in SF was almost normal in the EA, but NEA SF had significantly lower excretion levels. Urinary stones from endemic patients had higher fluoride, oxalate and calcium levels than those from non-endemic patients. In vitro studies suggested that fluoride did not influence the heterogonous mineralization of calcium oxalate. In conclusion, the data suggest that fluoride in vivo may behave as a mild promoter of urinary stone formation by (a) excretion of insoluble calcium fluoride, (b) increasing oxalate excretion and (c) mildly increasing the oxidative burden.