Recent experiments suggest the possibility of modulating the efficacy of cancer endocrine therapy by the pineal hormone melatonin (MLT). In particular, it has been demonstrated that MLT may stimulate estrogen receptor (ER) expression and enhance tamoxifen (TMX) effects other than the antiestrogenic action. Therefore, MLT could amplify the efficacy of TMX also in patients with negative ER. On this basis, a randomized study was performed with TMX versus TMX plus MLT in ER-negative metastatic breast cancer patients, who were unable to tolerate further chemotherapy, because of age, low performance status and/or heavy chemotherapeutic pretreatment. The study included 40 ER-negative post-menopausal, metastatic breast cancer patients, who were randomized to receive TMX alone (20 mg/day orally) or TMX plus MLT (20 mg/day orally in the evening). No complete response was seen. Partial response rate was significantly higher in patients treated with TMX and MLT than in those, who received TMX alone (7/19 vs 2/21, p<0.05). Moreover, the percent of survival at 1 year was significantly higher in patients treated with TMX plus MLT than in those treated with TMX alone (12/19 vs 5/21, p<0.01). No MLT-related toxicity was observed; on the contrary, most patients receiving MLT experienced a relief of anxiety and of depression. This preliminary study suggests that the association of the pineal hormone MLT may make TMX effective also in ER-negative metastatic breast cancer patients.