This double-blind study compared the clinical safety and parasitologic efficacy of single-dose regimens of diethylcarbamazine (DEC) and ivermectin for treatment of bancroftian filariasis in Papua New Guinea. Five groups of 10 men each with mean levels of parasitemia ranging from 2,985 to 5,185 microfilariae (mf)/ml were given DEC (6 mg/kg/ of body weight one time or 1 mg/kg, then 6 mg/kg four days later) or ivermectin (220 μg/kg; 20 μg/kg, then 200 μg/kg four days later or 20 μg/kg, then 400 μg/kg four days later). No significant side effects (e.g., acute adenolymphangitis, fever lasting more than eight hours, hypotension) were observed in any of the five treatment groups. The magnitude of reduction in microfilaremia was greater (P < 0.01) for the three ivermectin groups versus the two DEC groups in the first 30 days after drug administration (mf levels < 1% of pretreatment values versus 22.6-41.5%, respectively). At 90 and 180 days, mf levels continued to decrease in the DEC groups whereas they increased in the ivermectin groups given a total dose of 220 μg/kg. Eighteen months after drug administration, individuals given DEC or 420 μg/kg of ivermectin had the greatest degree of reduction in microfilaremia (86-90% compared with the pretreatment values). Decreases in parasite antigenemia measured by enzyme- linked immunosorbent assay for a secreted 200-kD adult worm antigen were greatest for the single-dose DEC group (39.7% decrease relative to the pretreatment level versus 7.8-15.7% for the ivermectin groups). These results indicate that single-dose DEC and ivermectin are well-tolerated by Wuchereria bancrofti-infected individuals with high levels of microfilaremia. Both drugs lead to sustained reductions in microfilaremia up to 18 months after administration.