Antibodies to phosphorylcholine and carbohydrate determinants responsible for much of the cross-reactivity among nematodes are subclass restricted in humans and absent in the IgG4 subclass. Total IgG and IgG4 antibody responses to Onchocerca volvulus were examined by enzyme immunoassay and by immunoblot. Significant background IgG reactivity was detected in both assays in US control sera and sera from patients with intestinal nematode infections, but background reactivity was negligible in the IgG4 assays. IgG4 antibodies were detected by enzyme immunoassay in 17 of 18 Nigerian onchocerciasis serum samples and in 2 of 9 endemic control serum samples. Cross-reactive IgG4 antibodies were present in serum pools from patients infected with other filariae. IgG4 antibodies recognized a restricted subset of O. volvulus antigens in immunoblots relative to IgG. These results confirm the previously reported enhanced specificity of IgG4 antibody assays for filariasis and extend the observation to include onchocerciasis. Whereas IgG4 subclass antibody serology is more specific than measurement of total IgG antibodies for onchocerciasis, cross-reactivity among filariae limits the utility of this approach.