BACKGROUND: Urinary tract stones (stones) are believed to be unusually common in the southeastern United States but neither the incidence of nor the risk factors for stones are known. METHODS: In three well-defined occupational populations in eastern Tennessee, we assessed the prevalence, incidence, and cumulative incidence of stones and measured biochemical risk factors for lithogenesis. RESULTS: The age-adjusted prevalence of stones was 18.5 percent in Tennessee compared to 7.7 percent among White males in US NHANES (prevalence ratio 2.4, 95% CI 1.7, 3.3). The cumulative incidence (risk) was 27.8 percent by age 65, higher than in any other reported population. Risk factors were age, a family history, and urinary saturation with calcium-oxalate (COAX). Persons with a positive family history and the highest measured CAOX index had a predicted lifetime risk of 88.8 percent. Biochemical factors affecting lithogenesis were hypercalciuria, hyperoxaluria, and low urine volume. CONCLUSION: Future research should characterize the geographic boundaries of a southeastern "stone-belt" and explore genetic and dietary hypotheses that might explain it.