We have previously demonstrated that the combination of tamoxifen and cisplatin has activity in patients with metastatic melanoma. In vitro studies have demonstrated that tamoxifen and cisplatin exhibit cytotoxic synergy in human melanoma cells and that this interaction is dependent on a tamoxifen effect. The mechanism of this effect is currently under investigation in in vitro studies. In an attempt to improve the complete response rate of this regimen, we initiated a phase II trial to determine the effect of the use of high dose tamoxifen and weekly cisplatin on the complete response rate, disease-free survival and overall survival. Tamoxifen was started on day 1 initially at a dose of 240 mg/day and continued until the patient was taken off treatment. This dose was subsequently lowered to 200 mg/day. Cisplatin (80 mg/m2) was begun on day 2 and repeated weekly for a total of 3 weeks. During week 4, the patient was not treated with cisplatin but was evaluated for response. If disease stabilization or regression was documented, the patient received a second 3 week cycle of cisplatin and was then re-evaluated for response. Patients with progressive disease at any evaluation were removed from the study. In 28 consecutive patients, the overall response rate was 32% (95% confidence interval 15.88-52.35%). One patient achieved a complete remission that lasted 22 months. All other responses were partial in nature. Toxicity was primarily nausea and vomiting. Two patients developed grade 2 renal toxicity. There were no episodes of deep venous thrombosis. This phase II study demonstrates that this combination has modest activity in patients with metastatic melanoma. However, this study failed to confirm our hypothesis that high dose tamoxifen would increase the complete response rate of this combination. While this combination has activity, the overall response rate is not significantly better that that observed with the original Dartmouth regimen and the toxicity is substantial. We do not recommend this dose and schedule for routine clinical use.