Human malignant lymphoma cells may be readily heterotransplanted into the brains of athymic nude mice. We have examined humoral immune responses to these lymphoma cells and have found a primary cytotoxic IgM and a late cytotoxic IgG response. Nude mice with tumors growing intracerebrally were injected intravenously with fractionated IgM or IgG anti-lymphoma cell antibody obtained from heterozygous immunocompetent animals. Frozen brain sections from these mice stained with fluoresceinated antibodies to mouse IgG and IgM revealed the presence of IgG but no IgM. Thus, IgM could not cross the blood-brain barrier to react with the heterotransplanted lymphoma cells. It is proposed that xenogeneic tumor cells grow readily within the brains of nude mice because these cells are protected from a primary host cytotoxic IgM response by the blood-brain barrier. The blood-brain barrier renders the brain an immune sanctuary within which the impaired cell-mediated immune responses of nude mice are further compromised by the exclusion of a major component of the humoral immune response.