IL–2 immunotherapy has been proven to be effective in the treatment of metastatic renal cell cancer (RCC). However, several drugs commonly used in the palliative therapy of cancer may potentially influence IL–2 efficacy, since the anticancer immunity has appeared to depend on complex interactions between immune system and psychoneuroimmunomodulation. In particular, experimental studies and preliminary clinical investigations have shown that the opioid substances, namely morphine, may suppress the anticancer immunity and the efficacy of IL–2 itself. In contrast, other neuroactive substances, in particular the pineal hormone melatonin (MLT), have been proven to stimulate the immune response, including the anticancer immunity, and to abrogate opioid–induced immunosuppression. On this basis, a study was planned to evaluate the effect of a concomitant MLT administration on the efficacy of IL–2 immunotherapy in advanced cancer patients chronically treated with morphine for cancer–related pain. The study was carried out in 30 metastatic RCC patients under chronic therapy with morphine at oral doses ranging from 60 to 120 mg/day. Patients were randomized to receive morphine alone or morphine plus MLT (20 mg/day orally in the evening). The immunotherapeutic cycle consisted of IL–2 subcutaneous administration at a dose of 6 million IU/day for 6 days/week for 4 consecutive weeks. In nonprogressing patients, a second cycle was planned after a 21–day rest period. The percent of partial responses achieved in patients treated with morphine alone was significantly lower than that observed in patients concomitantly treated with MLT (1/16 vs. 4/14, p<0.05). Moreover, the 3–year percent of survival was significantly higher in patients concomitantly treated with MLT (p<0.01). In contrast, no diminished analgesic efficacy of morphine occurred in patients concomitantly treated with MLT. This preliminary study seems to suggest that the negative influence of morphine therapy for cancer–related pain on the clinical efficacy of IL–2 cancer immunotherapy may be abrogated by the concomitant administration of the immunomodulating pineal neurohormone MLT.