With the observation of the occurrence of the human immunodeficiency virus (HIV) infection among leprosy patients in our pilot study carried out in Tamil Nadu, South India, a case-control study was planned to explore whether HIV infection is a risk factor for leprosy and to understand the characteristics of HIV infection and high-risk behaviors among leprosy patients. We screened 556 patients and 1004 nonleprosy controls (matching 502 cases for age, sex and area of residence) for HIV-1 and HIV-2 antibodies. They also were interviewed for personal information on history of blood transfusion, intravenous drug abuse, high-risk sexual behavior, and sexually transmitted diseases. Of the 1019 total cases screened (of both pilot and extended studies), 5 were found to be position for HIV antibodies (HIV-1 = 4, HIV-2 = 1); of the 1019 nonleprosy controls, 6 were positive for HIV-1 antibodies. An analysis by odds ratio revealed no association between leprosy and HIV infection (OR = 5.186, 95% CI = 1.717-15.667). However, unmarried, unmarried after 30 years of age, exposure to spouses of the leprosy patients, and a history of surgery were all observed to be significantly more common among leprosy patients than the controls.