Diethylcarbamazine (DEC) has been successfully administered to millions of people in established villages and towns, but little or no information exists on the use of this drug to control lymphatic filariasis in isolated seminomadic groups. We have studied the impact of biannual single-dose mass treatment to control filariasis in the Hagahai, an isolated hunter-gatherer, shifting horticulturist group in the fringe highlands of Papua New Guinea. Despite low treatment coverage, 6 mass treatment rounds significantly reduced the overall prevalence of infection with Wuchereria bancrofti, by antigen detection assay, from 55% before treatment to 34% after treatment. Obstructive filarial disease in the form of elephantiasis or hydrocele was not observed among the indigenous population. Anopheles species accounted for 91% of human-biting mosquitoes collected in the area. A total of 1126 mosquitoes were caught and dissected individually but none was infected with third-stage larvae (L3). Our findings support the phenomenon of facilitation, which predicts that Anopheles-transmitted lymphatic filariasis can be interrupted by mass chemotherapy alone in areas of low vector density and low transmission intensity as observed in the Hagahai.