To challenge the concept of protective immunity in lymphatic filariasis, 19 adult residents of a Wuchereria bancrofti-endemic island who had been diagnosed 17 years earlier as putatively immune endemic normals (PI/EN) were reexamined, Even with continued exposure to infection, all 19 had maintained their apparent infection-free status. Studies to define the mechanisms underlying this putative immunity revealed that cellular immune responses (including proliferation; generation of interleukin [IL]-2, IL-5, IL-10, interferon-gamma, and granulocyte-macrophage colony-stimulating factor) to adult- and microfilarial-stage antigens, hut not antibody responses, were markedly greater than those of 20 age-matched, infected patients. Furthermore, the PI/EN group was comprised of high- and low-responding persons who were clinically indistinguishable. These findings provide evidence that protective immunity to lymphatic filariasis does occur and that it is probably T cell-mediated.