Vaccination and infection can elicit protective and nonprotective antibodies to the fungus Cryptococcus neoformans in mice. The effect of nonprotective antibodies on host defense is unknown. In this study we used mixtures of protective and nonprotective monoclonal antibodies (mAbs) to determine if nonprotective mAbs blocked the activity of the protective mAbs. Antibody isotype and epitope specificity are important in determining the ability to prolong survival in mice given a lethal C. neoformans infection. Three different nonprotective immunoglobulin (Ig) G3 mAbs to cryptococcal capsular polysaccharide were used to study the interaction between the IgG3 isotype and protective IgG1 and IgG2a mAbs in murine cryptococcal infection. One IgG3 mAb reduced the protective efficacy of an IgG1 with identical epitope specificity. A second IgG3 mAb with different epitope specificity also reduced the protection provided by the IgG1 mAb. The protective efficacy of an IgG2a mAb was also dramatically decreased by still another IgG3 mAb. To our knowledge this is the first report of blocking antibodies to a fungal pathogen. The results have important implications for the development of vaccines and passive antibody therapy against C. neoformans.