Antibody response to feeding by the horn fly, Haematobia irritans irritans (L.), was measured in naturally infested cattle as well as in controlled infestations. Humoral antibody level was not correlated with fly abundance in natural infestations. Correlations between the antibody response and fly abundance were extremely variable among animals. Antibody response to horn fly salivary antigens peaked within 4 wk after fly abundance reached 150 flies per animal. In controlled infestations, antibody response was weak during an initial exposure to 200 flies per animal, but increased after flies were removed from the cattle. Horn fly salivary antigen may have an immunomodulatory effect on the host.