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The epidemiology of leprosy in rural Egypt is unknown. This prospective household survey was conducted in a high-prevalence Egyptian village in order to explore the epidemiologic characteristics of the disease and to determine the possible socioeconomic and HLA genotype risk factors.The subjects of the study were the residents of Kafr-Tambul village in the Dakahlia governorate, Egypt. There were 10,503 inhabitants of the village, of whom 9643 (91.8%) had a complete visual skin examination, and suspected leprosy patients were subjected to histopathological examination and slit skin smears. Each household was interviewed to record personal data on family members, family size, education, occupation, crowding index at sleep, social score and source of water supply. Human leukocyte antigen (HLA) class II genotypes were analyzed in all leprosy patients and in a number of both household (N = 124) and non-household (N = 30) contacts.The overall prevalence of clinical leprosy in the village studied was 24.9/10,000 (95%CI = 16.3–37.6). Individuals above the age of 40 years were 4 times more likely to develop leprosy (OR = 4, P = 0.01). The degree of education, crowding index at sleep, social score and source of water supply were found to be unlikely to increase the risk of leprosy (P > 0.05). The frequencies of HLA-DR2 and -DQ1 were significantly associated with leprosy (OR = 3.33 and 5.4; CI = 0.95–12.07 and 1.08–30.19, respectively, all P < 0.05).Our study provides the first picture of the epidemiology of leprosy in a high-prevalence village in rural Egypt. Leprosy detection campaigns should be initiated and directed towards high-prevalence villages. Provision of leprosy control activities in rural health units is necessary in order to detect new cases. The risk for leprosy is associated with HLA-DR2 and -DQ1 markers, and these markers appear to increase personal susceptibility to leprosy in this village.