Leprosy is a debilitating chronic disease caused by infection with Mycobacterium leprae. A World Health Organization-directed control strategy based upon the identification and treatment of patients has resulted in a marked reduction in the number of registered worldwide leprosy cases over the last 20 years. Despite these efforts, the number of new leprosy cases detected each year now remains relatively stable, and M. leprae infection continues to pose a health problem. It is suggested that earlier diagnosis is required to strengthen control programs. In this study, we have examined the development of antigen-specific immunoglobulin responses within armadillos experimentally infected with M. leprae to identify those responses that develop most rapidly and robustly following infection. Antibody responses to the M. leprae-specific phenolic glycolipid I and several protein antigens previously demonstrated to have diagnostic potential were assessed. Our results identify several antigens that can provide early diagnosis of M. leprae infection but also indicate considerable variability in the development of antigen-specific antibodies. Our data suggest that a combination of antigens is likely required to provide accurate and early leprosy diagnosis.