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The presence of circulating microfilariae has been associated with alterations in B and T cell functions. In this study, we compared the influence of diethylcarbamazine (DEC) and ivermectin on filarial antigen-specific immune responses in a Haitian population. Both drugs were effective at reducing microfilaremia levels to less than 10% of pretreatment levels for up to one year. This reduction in microfilaremia was associated with two phases of altered cellular responsiveness monitored with in vitro assays. Five days post-treatment, cellular proliferation in response to both filarial and nonfilarial antigens was significantly increased, as was the background response in the absence of any antigen. At both nine months and one year post-treatment, the filarial antigen-specific reactivity of both DEC- and invermectin-treated patients was significantly increased over baseline levels. No differences were observed between the two treatment groups in terms of humoral or cellular reactivity to filarial antigens, despite evidence suggesting a role for DEC in adult worm killing. These results provide additional evidence that microfilariae modulate antifilarial immune reactivity.