Neonatally thymectomized Lewis rats (NTLR) were shown to be highly susceptible to infection with Mycobacterium leprae. We have used them in chemotherapeutic studies as models of human lepromatous leprosy. NTLR chronically infected with M. leprae were treated with various regimens combining a background of the minimal effective dose (MED) of dapsone (4,4'-diaminodiphenylsulfone, DDS) or 100 times this dose in the diet with one to ten doses of rifampin (RMP) of 10 mg/kg. To test for persisting viable M. leprae passage of 5 X 19(3) organisms was made to intact mice, and 10(5) to 10(7) acid-fast bacilli were passaged to NTLR. The only regimen that appeared to be completely effective in eliminating infectivity for intact mice was ten doses of RMP given on the background of the MED of DDS. No viable organisms were detected in any passage mice, but multiplication of M. leprae was detected in 12 of 16 passage NTLR, representing three of the four groups in which passage was made. In no instance did we fail to detect organisms in passage of NTLR when we detected them in passage mice, and multiplication was demonstrated in passage NTLR in 14 instances in which M. leprae failed to multiply in passage mice. Because of its high degree of immunosuppression, the NTLR was able to detect a small population of viable M. leprae in inocula containing up to 5000 times the number of organisms that can be inoculated into intact mice. The NTLR appears to provide a model for the study of microbial persistence in leprosy.