Homozygous possession of the single autosomal recessive gene, lpr (lymphoproliferation) is associated with increased susceptibility to acute infection with Trypanosoma cruzi in four congenic strains of mice (Boyer et al., 1983, Parasit. Immunol. 5: 135-142). Animals bearing the lpr gene, which controls certain autoimmune and lymphoproliferative manifestations (Murphy and Roths, 1978. In Genetic Control of Immune Disease, N. R. Rose, P. E. Bigazzi, and N. L. Warner (eds.). Elsevier North Holland, Amsterdam, pp. 207-220), show increased parasitemia or mortality when compared to their congenic partners that lack the gene. In the study described here we sought to determine if possession of the lpr gene might also influence susceptibility to another protozoan parasite, Leishmania tropica. Our data indicate that female MRL/MpJ-lpr mice injected with L. tropica promastigotes are susceptible to the infection, whereas their congenic partners, MRL/MpJ-+, are resistant to an identical dose of parasites. Because the two strains are of the same haplotype (H2k) and differ only in possession of the lpr gene, our results suggest that this single, non-H2-associated gene can influence susceptibility to infection with L. tropica. Leishmania tropica (WR 309) amastigotes were aspirated by needle from the lesions of infected BALB/cJ mice and allowed to transform into promastigotes. Eight-wk-old female MRL/ MpJ-lpr and MRL/MpJ-+ mice (Jackson Laboratory) were infected via subcutaneous injection of 5 x 107 organisms into the left rear footpad. The right rear footpad was injected at the same time with phosphate-buffered saline and footpad measurements (mm) made weekly with a Pocotest micrometer. The measurements on the MRL strains and additional C57BL/6J and BALB/cJ animals were expressed as the ratio between right and left footpad thicknesses. As seen in Figure 1 the two congenic MRL strains responded differently to infection with L. tropica. The MRL/MpJ-lpr mice were unable to control the parasites and showed a slow progressive expansion of the lesion. This result, albeit less pronounced than that found in L. tropica-sensitive BALB/cJ (H2d) mice is similar to that reported in DBA/1 animals (H2q) (Howard et al., 1980, Parasit. Immunol. 2: 303-314). Surviving MRL/MpJ-lpr animals also had metastatic lesions. MRL/MpJ-+ mice showed a pattern of lesion development similar to that of C57BL/6J (H2b) animals. Data on the genetic factors that influence susceptibility to L. tropica infection indicate substantial differences between mouse strains (Cox, 1981, Nature 291: 111-112). These differences appear to be largely H2-independent, although a certain retarding influence of H2k on the later stages of lesion growth has been observed in animals with the susceptible BALB/c (H2d) background (Howard et al., 1980, op. cit.). The hypersusceptibility of BALB/c mice is determined