This phase II trial examined the efficacy and toxicity of first-line treatment with everolimus, paclitaxel, and carboplatin in patients with advanced melanoma. Seventy patients with metastatic or locally advanced unresectable melanoma who had been untreated previously with chemotherapy or targeted agents received first-line treatment with everolimus (5 mg, orally, daily), paclitaxel (175 mg/m, intravenous, every 3 weeks), and carboplatin (area under the curve 6.0, intravenous, every 3 weeks). Response to treatment was assessed every 6 weeks; responding and stable patients received six cycles of paclitaxel and carboplatin, and subsequently continued single-agent everolimus until disease progression or unacceptable toxicity. Twelve patients (17%) showed objective responses (all partial); an additional 27 patients showed measurable tumor shrinkage. After a median follow-up of 15 months, the median progression-free survival was 4.0 months (95% confidence interval 2.8-5.0 months); the median survival for the entire group was 10.1 months. Myelosuppression was the most common grade 3/4 toxicity; 70% of patients experienced at least one episode of grade 3/4 toxicity while on study. Although this regimen was active in the first-line treatment of advanced melanoma, there was no suggestion of improved efficacy when compared with previous results with paclitaxel/carboplatin alone. Further study of this combination is not recommended.