High titers of antibodies against Anopheles gambiae midguts were produced in New Zealand rabbits to identify midgut targets for an antimosquito vaccine. The serum from one of 8 rabbits (designated R2B6) killed 71.6% (Abbott's adjusted % mortality) of An. gambiae within 7 days. Mosquitoes ingesting R2B6 serum were unable to absorb their blood meal nutrients, resulting in reduced oviposition and egg hatching rates. Anopheles stephensi and Anopheles arabiensis were also killed when ingesting R2B6 serum but Anopheles freeborni, Anopheles albimanus, and Aedes aegypti were not affected. The mosquitocidal factor was a relatively large molecule (> 100,000 MW) maintained at threshold levels in the sera and killing was complement independent. Mortality, however, was not IgG mediated, as determined by protein A-sepharose fractionation. This surprising finding confounds possibilities of using antibodies against whole mosquito midguts as a step in the development of antimosquito vaccines.