In order to understand natural resistance to filariasis, we compared Litomosoides sigmodontis primary infection of C57BL/6 mice, which eliminate the worms before patency, and BALB/c mice, in which worms complete their development and produce microfilariae. Our analysis over the first month of infection monitored migration of the infective larvae from the lymph nodes to the pleural cavity, where the worms settle. Although immune responses from the mouse strains differed from the outset, the duration of lymphatic migration (4 days) and filarial recovery rates were similar, thus confirming that the proportion of larvae that develop in the host species upon infection is not influenced by host genetic variability. The majority of worms reached the adult stage in both mouse strains; however, worm growth and molting were retarded in resistant C57BL/6 mice. Surprisingly, the only immune responses detected at 60 h postinfection occurred in the susceptible mice and only upon stimulation of cells from lymph nodes draining the inoculation site with infective larva extract: massive production of interleukin-6 (IL-6) and IL-5 (the latter cytokine was previously suspected to have an effect on L. sigmodontis growth). However, between days 10 and 30 postinfection, extraordinarily high levels of type 1 and type 2 cytokines and expansion of pleural leukocyte infiltration were seen in the resistant C57BL/6 mice, explaining the destruction of worms later. Our results suggest that events early in the infection determine susceptibility or resistance to subsequent microfilarial production and a parasite strategy to use specific immune responses to its own benefit.In areas where filariasis is endemic, a small proportion of the population (Ͻ5%) consistently shows neither microfilariae nor pathology. Characterization of the protective mechanisms operating in this putatively immune population is highly desirable and has consequently received great attention (18,23,41,46,47,50). However, experimental investigations or field observations aiming to correlate parasitological, immunological, and genetic factors with resistance in humans are limited for evident ethical reasons. The filaria Litomosoides sigmodontis has proven to be a good murine model (1,8,42), since in various strains of mice it mimics the spectrum of parasitological outcome of human filariasis (42). Recently, genetically modified mice have been employed to rapidly identify key immune components; the absence of Th2 (28, 48, 49) or Th1 (gamma interferon [IFN-␥]) (44) cytokines as well as of B cells and antibodies (2, 35) has been shown to modify L. sigmodontis development or survival, as observed in the nonpermissive Brugia models (6,14,27,43). However, the inherent physiological and immunological artifacts that can occur in deficient mice sometimes limit the interpretation of the results.Two previous studies compared the splenic and antibody responses to L. sigmodontis in genetically intact susceptible BALB/c mice to those in resistant B10D2 (33) or C57BL/6 (28) mice. No clear d...