Crimean-Congo hemorrhagic fever (CCHF) virus is widely distributed in wild and domestic mammals, birds, and ticks throughout many regions of Africa, Europe, and Asia. Interviews were conducted with 484 individuals from nine farms in the Republic of South Africa from which recent human CCHF cases had originated and with individuals from 27 farms without recognized cases. Serum samples were obtained from all consenting individuals. Blood was also drawn from 2,212 farm animals. Human infection with CCHF virus was uncommon (point prevalence 12.6/1,000). Antibody prevalence in humans on farms increased with age (P less than 0.001), and was correlated with handling lambs. Overall, a greater number of older animals were antibody positive than animals less than one year of age (P less than 0.001), but 12.7% of young animals on farms with human were antibody positive compared with 5.8% on those farms without human infection (P less than 0.05). Physical contact with ticks or tick bite was also found to be a risk factor, but contact with animal blood or fresh meat was not. The risk of CCHF virus infection in the community increased seven-fold following contact with a recognized CCHF case, even when other risk factors were taken into account (point prevalence rate 4.7%). In contrast, antibody prevalence was less than 1% (1 of 128) in the local hospital staff who had cared for patients with CCHF. Prevention is best achieved by education of the farming community and establishing and maintaining awareness in the hospital staff.