Background. The efficacy of doxycycline for treating the causal agent of human lymphatic filariasis, Brugia malayi, is unknown. Standard treatment with diethylcarbamazine-albendazole is associated with adverse reactions. We assessed whether doxycycline alone or in combination with diethylcarbamazine-albendazole would lead to sustained amicrofilaremia and reduced incidence of adverse reactions. Methods. A double-blind, randomized, placebo-controlled 6-week field trial of doxycycline treatment (100 mg/day) of 161 persons infected with B. malayi was conducted. Four months after receiving doxycycline (n = 119) or placebo (n = 42), participants received diethylcarbamazine (6 mg/kg) plus albendazole (400 mg) or a matching placebo. Adverse reactions were assessed 48 and 60 h after administration of diethylcarbamazine-albendazole. Treatment efficacy was evaluated at 2, 4, and 12 months after the initial doxycycline treatment. Results. Four months after beginning doxycycline treatment, Wolbachia loads were reduced by 98%. Doxycycline treatment reduced the prevalence of microfilaremia at 2, 4, and 12 months of follow-up (P < .001 for all time points). At the 1-year follow-up, prevalence was reduced by 77% and 87.5% in patients receiving doxycycline alone or doxycycline plus diethylcarbamazine- albendazole, respectively. In contrast, the reduction of microfilaremia in the group receiving placebo doxycycline plus diethylcarbamazine-albendazole was merely 26.7%. Adverse reactions were lowest in the group receiving doxycycline plus placebo diethylcarbamazine-albendazole and highest in the group receiving placebo doxycycline plus diethylcarbamazine-albendazole. The proportion of persons with high fever and severe adverse reactions was significantly reduced in the group treated with doxycycline plus diethylcarbamazine-albendazole. Conclusions. A 6-week course of doxycycline, either alone or in combination with diethylcarbamazine-albendazole, leads to a decrease in microfilaremia and reduces adverse reactions to antifilarial treatment in B. malayi-infected persons.