Postimmunization human B lymphocytes and mouse myeloma cells were fused to produce interspecies hybridomas secreting human antibody of predefined specificity with an initial frequency comparable to intraspecies fusion. After 13 mo in culture, one clone continued to secrete high titers of human IgG antitetanus toxin antibody. This antibody binds to the B fragment of tetanus toxin and protects mice against tetanus. The demonstration of in vivo protection with a human monoclonal antibody is an important first step towards the ultimate goal of human administration of monoclonal antibodies for the prevention and therapy of human infections.