Cancer-bearing patients exhibit a variety of profound T-cell abnormalities which include decreased cytotoxic capacity as measured by allogeneic cell-mediated lympholysis (CML), natural-killer (NK) cell activity, and decreased lymphokine production. In patients with advanced solid malignancies, allogeneic CML, tested by a 4-hr 5'Cr-release assay, was significantly lower than in a group of normal individuals. If optimal doses of affinity-purified prothymosin a (ProTa) were present during mixed lymphocyte culture, the CML of cancer patients was increased almost to normal levels. Mixed lymphocyte reaction, tested by tritiated thymidine uptake, was also decreased in these patients and was enhanced to normal levels if ProTa was added to the cultures. NK activity was decreased in these patients according to %r-release assays. ProTa increased the NK activity up to normal levels. The reduced NK and CML activities in cancer patients were associated with abnormal production of prostaglandin E2 (high) and interleukin-2 (low), which were to a great extent normalized in the presence of ProTa. These results demonstrate that ProTa is capable of potentiating or fully restoring the deficient cytotoxic effector function of peripheral mononuclear cells (MNC) in patients with advanced malignancies.