Optimal treatment for cancer of unknown primary (CUP) can challenge clinicians. This study sought to determine the efficacy and toxicity of weekly paclitaxel and carboplatin in CUP. Forty-two subjects enrolled. Treatment was intravenous paclitaxel (80 mg/m2) plus carboplatin (AUC = 2) on Days 1, 8, and 15 every 28 days. Seven (18 percent) responded (complete = 2, partial = 5); median survival was 8.5 months; estimated survival (12 and 24-month) was 33 and 17 percent, respectively. Median time to progression was 3.7 months, and estimated progression-free survival (12 and 24 months) was 14 and 7 percent, respectively. Median duration of response was 17.3 months. This combination produced modest antitumor activity in advanced CUP.