This study evaluated the impact of leprosy multidrug therapy (MDT) on cell-mediated immunity (CMI) and antibody responses at diagnosis in untreated paucibacillary (PB) (n=15) and multibacillary (MB) patients (n=15) using a panel of Mycobacterium leprae recombinant antigens (rMLs) (CMI: 46f, ML0276, ML2055, leprosy IDRI diagnostic 1 [LID-1], and ML2629, as negative control; serology: LID-1, 46f, 92f, and 33f, as negative control, and phenolic glycolipid I [PGL-I]) and at 2 time points after MDT (PB: 8-20months; MB: 4-22months). At diagnosis, PB patients produced interferon gamma (IFNγ), and MB patients exhibited low/absent response. Shortly after MDT, IFNγ production in PB patients declined except for LID-1; MB patients produced IFNγ to LID-1. Almost 2years after MDT, IFNγ levels declined in PB and MB patients. Most untreated PB patients were seronegative to PGL-I and rML, remaining so after MDT. Most untreated MB patients were seropositive to all antigens, and IgG to rMLs declined after MDT. Reduction in antigen-specific CMI in PB and in antibody response in MB patients may help monitor MDT effectiveness.