A matched case-control study (95 cases and 220 controls) was designed to study risk factors for atypical scrapie in sheep in France. We analyzed contacts with animals from other flocks, lambing and feeding practices, and exposure to toxic substances. Data on the prnp genotype were collected for some case and control animals and included in a complementary analysis. Sheep dairy farms had a higher risk for scrapie (odds ratio [OR] 15.1, 95% confidence interval [CI] 3.3-69.7). Lower risk was associated with organic farms (OR 0.15, 95% CI 0.02-1.26), feeding corn silage (OR 0.16, 95% CI 0.05-0.53), and feeding vitamin and mineral supplements (OR 0.6, 95% CI 0.32-1.14). Genetic effects were quantitatively important but only marginally changed estimates of other variables. We did not find any risk factor associated with an infectious origin of scrapie. Atypical scrapie could be a spontaneous disease influenced by genetic and metabolic factors.