In vitro lymphocyte reactivity (LR) to phytohemagglutinin and peripheral blood thymus-dependent lymphocyte (T cell) levels were determined in 42 tumor-bearing patients with clinically operable melanoma and were compared to 41 age-matched normal controls. Patients with tumors clinically confined to the primary site (Stage I) as a group had normal immune reactivity and T cell levels, and those with regional metastases by clinical assessment (Stage II) had relatively impaired LR and T cell levels. In 6 of 24 patients with clinical Stage II tumors, widespread metastases (Stage III) subsequently were found. The severe immune defects in this group with occult disseminated melanoma accounted for the impaired LR and low T cell levels in the group with clinical Stage II tumors. Although overlapping levels of LR and T cells in the patients with pathological State II and III tumors prevent use of the data as a determinant of tumor extent in individual patients, these in vitro assays apparently define a relation between cellular immunocompetence and tumor burden in patients with melanoma.