The effect of tumor growth on the suppressor cell activity of melanoma patients was examined by measurement of immunoglobulin produced in vitro in pokeweed mitogen (PWM)-stimulated cultures of B and T lymphocytes. B and T cells were separated by sheep red blood cell rosetting and suppressor cell activity was assessed by comparison of immunoglobulins produced in cultures with irradiated T cells (2,000 rads) to that with unirradiated T cells. In the majority of patients with localized melanoma, radiosensitive suppressor T cells were detected and appeared to be an augmentation of a normal physiological state. In patients with Stage I and II melanoma, removal of the tumor resulted in a significant decrease in suppressor activity against IgA and IgM but not against IgG production. Similar sequential changes in suppressor cell activity against IgA and IgM but not against IgG production. Similar sequential changes in suppressor cell activity were not generally detected in patients who had surgery for skin graft after previous removal of the primary melanoma or in patients undergoing surgery for non-malignant conditions. Sequential studies on the levels of serum immunoglobulins showed an apparent trend for immunoglobulins to increase after surgery. Of particular importance, the decrease in in vitro suppressor cell activity against IgM and IgG production after tumor removal in individual patients was significantly associated with an increase in immunoglobulin levels in the serum of these patients. It is suggested that these findings may account in part for the absence of detectable antibody responses to melanoma antigens in many patients and for the generalized immunodeficiency in patients with disseminated melanoma.