IgG subclass responses to Mycobacterium leprae 18,000 MW recombinant antigen (18K) were determined in sera from untreated leprosy patients using an ELISA-based assay with specific monoclonal antibodies. Antibodies to M. leprae 18K were restricted to IgG1 and IgG3 antibodies with higher seropositivity in lepromatous patients (25.5% for IgG1 and 12.8% for IgG3) compared to patients with tuberculoid disease (11.5% for IgG1 and 5% for IgG3). No significant antibody response was detectable in IgG2 and IgG4 in patients with either lepromatous or tuberculoid leprosy. The selective production of antibodies in IgG1 and IgG3 subclasses could not be related to polyclonal activation in these subclasses as all IgG subclasses showed similar elevated levels at the polyclonal level. The major difference noted between lepromatous and tuberculoid leprosy patients with the IgG subclass antibody response was a strong linear correlation between IgG1 and IgG3 responses to M. leprae 18K in lepromatous patients (r = 0.703, P < 0.001) but not in tuberculoid leprosy patients (r = 0.007, P > 0.10) which may be related to immunoglobulin class switching of IgG3 to IgG1 rather than selective shifts in T-helper subsets. Our results therefore, do not support the hypothesis that activation of Th2 cells occurs in lepromatous leprosy; this issue needs further examination.