The clinical manifestations and geographic distribution of loiasis overlap with those of other human filarial parasites, presenting challenges in the specific diagnosis of loiasis that may lead to delays in appropriate therapy. A recombinant antigen (Ll-SXP-1), preferentially recognized by serum samples from experimentally infected rhesus monkeys, was identified from a Loa loa L3 cDNA library. IgG4 antibody reactivity to purified Ll-SXP-1 was assessed by means of ELISA, using serum samples from patients with loiasis, lymphatic filariasis, onchocerciasis, mansonellosis, or other helminthiases and healthy control subjects. The assay was 56% sensitive and 98% specific for loiasis. Antibody reactivity was detectable before microfilaremia in experimentally infected rhesus monkeys and declined (but did not disappear) after diethylcarbamazine therapy in infected patients. IgG4 antibodies to recombinant Ll-SXP-1 are a highly specific marker of L. loa infection and may be useful for the diagnostic evaluation of persons with filariasis of unclear etiology.