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.