Wild nine-banded armadillos (Dasypus novemcinctus) in the south central United States are highly endemic natural hosts of Mycobacterium leprae. Surveys conducted over the last 30 years on more than 5000 animals confirm that the infection is present among armadillos in Arkansas, Louisiana, Mississippi and Texas. Highest prevalence rates are found among the animals in low-lying alluvial and coastal areas, primarily in Louisiana and Texas. Both animal density and local factors may contribute to the detectability of armadillo leprosy in those regions. Little evidence for M. leprae infection is found among armadillos elsewhere in the US range, and only a few reports relate finding the infection among animals in Central or South America. However, the issue has received only scant attention in other countries. Armadillos only recently expanded their range into the US, and leprosy was present in Texas and Louisiana prior to the arrival of armadillos. The ecological relationship between humans and armadillos with M. leprae in this region remains unclear. However, infected armadillos constitute a large reservoir of M. leprae and they may be a source of infection for some humans in this country, and perhaps in other locations across the animal's range.