Lymphocyte responses to the mitogens concanavalin A (Con A) and phytohemagglutinin (PHA) are important in vitro parameters of immunocompetence in cancer patients. The tempo and intensity of this response is regulated by monocytes. We found that the blood lymphocyte response to one or both of these mitogens was significantly depressed in 32 of 33 melanoma patients compared to 29 normal control subjects. However, these responses were significantly enhanced when the drug indomethacin, a prostaglandin synthetase inhibitor, was added to cultures of peripheral blood mononuclear cells (PBMCs) from the melanoma patients, but not from the normal control subjects. For example, at a 1 microgram/ml dose of Con A, the mean response of melanoma patients increased from 56% to 81% of the normal mean response, whereas at 20 micrograms/ml PHA the mitogen response increased from 57% to 77% of normal when PMBC were incubated with indomethacin (P less than 0.001). Overall, indomethacin enhanced the mitogen responses of melanoma patients by 35% to 85%, whereas indomethacin increased the response in normal subjects by only 5% to 15%. The mitogen response of monocyte-depleted ER+ lymphocytes for melanoma patients was equivalent to that of normal control subjects, and there was no enhancement of this response in the presence of indomethacin. This suggests that the abnormality was due to an altered function of immunoregulatory monocytes. The enhancement by indomethacin in melanoma patients was not significantly influenced by their stage of disease, age, or the proportion of blood monocytes. The decreased levels of cellular immunocompetence in these melanoma patients, as measured by their lymphocyte proliferative responses to mitogens, therefore appears to be associated with an abnormality in monocyte function that is partially corrected by indomethacin.