Pooled sera from leprosy patients across the clinical spectrum, tuberculosis patients and healthy individuals were tested for their reactivity with antigens of Mycobacterium leprae and a panel of cultivable mycobacteria by immunoprecipitation technique. Sera from lepromatous leprosy patients demonstrated exclusive reactivity with the 26-kDa protein of M. tuberculosis H37Ra, 28-kDa protein of M. kansasii, 45-kDa protein of M. smegmatis, and 158, 40 and 14 kDa proteins of M. phlei. Sera from patients with borderline tuberculoid leprosy, tuberculoid leprosy, tuberculosis and health individuals failed to identify these antigens. Our studies indicate that analysis and characterization of immunodominant antigenic epitopes present on proteins of cultivable mycobacteria, sharing cross-reactive epitopes with M. leprae may prove to be important in the serodiagnosis of multibacillary leprosy as well as for developing vaccines for immunotherapy of leprosy.