Intradermal (i.d.) immunization of Lewis rats with autoclaved Mycobacterium leprae resulted in antigen-specific proliferation responses and interleukin-2 release from spleen and lymph node cells that were detectable as early as 21 days, persisted for at least 9 months, and were dependent on the dose of antigen administered. Immunized animals were also completely resistant to a footpad challenge with viable M. leprae. In contrast, intravenous (i.v.) administration of at least 10(8) irradiated M. leprae isolates induced a state of nonresponsiveness characterized by the absence of proliferation and interleukin-2 release by antigen-stimulated lymphoid cell cultures; however, in vitro responses to mitogenic stimulation and in vivo responses to keyhole limpet hemocyanin and Listeria monocytogenes were normal. Animals that received an i.v. injection of M. leprae remained nonresponsive to M. leprae antigens even after a subsequent i.d. immunization. This state of nonresponsiveness persisted for at least 6 months after induction. Results of footpad challenge experiments showed that the ability of animals rendered nonresponsive by an i.v. injection of M. leprae to control the growth of viable M. leprae in the footpad was not different from that of untreated rats. In addition, animals receiving an initial i.v. injection and a subsequent i.d. immunization with M. leprae were not protected from a viable challenge, as were rats that received only i.d. immunization. These results suggest that i.v. administration of a large dose of M. leprae to rats induces a state of nonresponsiveness to M. leprae antigens that may be similar to that seen in lepromatous leprosy patients.