Antifungal therapy cannot eradicate Cryptococcus neoformans infections in immunosuppressed patient groups. Therefore, adjunctive antibody-based therapy is being considered to enhance host immune responses to C. neoformans. To characterize potentially protective reagents, the idiotypic repertoire of human antibodies to cryptococcal glucuronoxylomannan (GXM) elicited by the investigational conjugate vaccine GXM-tetanus toxoid was examined. The variable genes used by human antibodies to GXM were analyzed with an antigen-based ELISA and mouse monoclonal antibodies (MAbs) that recognize determinants of human VH1, VH3, and VH4 gene segments. Antibodies to GXM were shown to use VH3 gene segments, and antibodies with the greatest binding to GXM also bound to protein A. A VH3-positive human monoclonal IgM prolonged survival of C. neoformans-infected mice. This is the first report that a human antibody is protective against C. neoformans. These results suggest that human MAbs may have promise as therapeutic reagents against cryptococcosis.