Diethylcarbamazine (N,N-diethyl-4-methyl-1-piperazine carboxamide; DEC) is a drug frequently used for prevention and treatment of the filariases. An opsonic action of DEC may generate increased immune responses to microfilariae. We tested the hypothesis that DEC treatment could result in higher antibody levels to other infectious agents. A retroviral animal model was studied, in light of the consideration that use of DEC as an antifilarial agent could conceivably alter seroepidemiologic surveys as well as serologic outcomes of vaccine trials in Africa regarding human immunodeficiency virus (HIV). The effect of DEC treatment on serum antibody to feline oncornavirus-associated cell membrane antigen (FOCMA) in domestic cats exposed to feline leukemia virus (FeLV) was examined. Nine cats that tested negative before treatment tested positive (greater than or equal to 1:10 serum dilution, geometric mean titer [GMT] = 278) for antibody to FOCMA after DEC treatment. Among 19 cats initially testing positive for FOCMA antibody, higher titers were noted after treatment in 17 (pretreatment GMT = 264; posttreatment GMT = 6,158). We conclude that a history of DEC treatment should be considered in evaluating humoral responses to infectious agents. Whether use of ivermectin, a recently introduced antifilarial agent, in lieu of DEC will affect clinical expression of HIV infection in humans also warrants analysis.