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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. Leprosy is caused by infection with the bacterium Mycobacterium leprae, and its clinical symptoms, bacterial burdens, pathology, and underlying immunological responses vary widely. Diagnosis is complicated due to this wide range of signs but can be arranged histologically into the five distinct categories of the Ridley-Jopling scale (polar tuberculoid [TT], borderline tuberculoid [BT], mid-borderline [BB], borderline lepromatous [BL], and polar lepromatous [LL]) (22, 24). The World Health Organization (WHO) has suggested diagnosis of leprosy be made by the observation of one or more of the following: hypopigmented or reddish skin patches with definite loss of sensation; thickened peripheral nerves; and acid-fast bacilli on skin smears/biopsy specimens. In the classification based on skin smears, patients showing negative smears at all sites are grouped as paucibacillary (PB) leprosy, while those showing positive smears at any site are grouped as multibacillary (MB) leprosy. In practice, most programs use the clinical criteria for classifying and selecting the treatment regimen for individual patients. The clinical system includes counting the number of skin lesions and nerves involved as the basis for grouping leprosy patients into the PB (less than 5 lesions) and MB (typically 5 or more lesions) categories. It would be highly beneficial to identify M. leprae infection before such signs appear. It is believed that a significant number of individuals contain infection such that it remains subclinical or self-cures with