Fungal infections have been increasing and life-threatening in recent years, but host immune responses, especially the humoral immunity, to fungi have not been fully understood. In the present study, we report that natural antibodies from unimmunized mice bind to Candida albicans. We established a monoclonal natural antibody, 3B4, which recognized a surface antigen located at germ tubes of C. albicans. The 3B4 antibody protected mice from C. albicans-induced death in passive immunization, by mechanisms involving suppressing germ tube formation and modulating phagocytosis. Interestingly, 3B4 also bound to a self-antigen keratin. To further study the generation and anti-C. albicans activities of natural antibodies in vivo, we constructed a mu chain transgenic mouse (TgV(H)3B4) using the V(H) gene from 3B4. TgV(H)3B4 had elevated serum anti-keratin/C. albicans IgM, and were resistant to C. albicans infections. Analyses of B cell development showed that in TgV(H)3B4, B cells secreting the anti-keratin/C. albicans antibodies were enriched in the B1 B cell compartment. Our findings reveal an important role of keratin-reactive natural antibodies in anti-C. albicans immune responses, and suggest that keratin may function in selecting B cells into the B1 B cell compartment, where natural antibodies are made to fight fungal infections.