Identification of antigenic determinants of the polar immune response in leprosy may illuminate both protection and pathogenesis. Thirty subjects were studied (22 with polar disease and 8 healthy controls who were heavily exposed but disease-free) by assaying the proliferative, interferon (IFN)-gamma, and antibody responses to recombinant antigens of Mycobacterium leprae (10, 28, 36, and 65 kDa). The 10-kDa antigen elicited IFN-gamma production from all tuberculoid (TT) and borderline tuberculoid (BT) patients but little from controls, lepromatous (LL), or borderline lepromatous (BL) patients (P<.05). Production of 65-kDa-specific IFN-gamma was higher in TT/BT than in controls or LL/BL patients (P<.006). All subjects produced 65-kDa-specific antibody, but it was higher in LL/BL patients than in healthy controls, whose responses were higher than in TT/BT subjects (P=.035). The 36-kDa antibody responses were selectively increased in LL/BL subjects (P<.02). The intermediate phenotype of the controls suggests that M. leprae-specific production of IFN-gamma may contribute to pathology and to protection in leprosy.