BACKGROUND The objective of this study was to evaluate the efficacy of belinostat, a histone deacetylase inhibitor, when added to paclitaxel/carboplatin in the empiric first‐line treatment of patients with carcinoma of unknown primary site (CUP). METHODS In this randomized phase 2 trial, previously untreated patients with CUP were randomized to receive belinostat plus paclitaxel/carboplatin (group A) or paclitaxel/carboplatin alone (group B) repeated every 21 days. Patients were re‐evaluated every 2 cycles, and those without disease progression continued treatment for 6 cycles. Patients in group A then continued receiving single‐agent belinostat, whereas patients in group B stopped treatment. The primary endpoint was progression‐free survival (PFS): The authors postulated that the addition of belinostat would improve PFS from 5 months (expected with paclitaxel/carboplatin) to 8 months. RESULTS In total, 89 patients were randomized (group A, n = 44; group B, n = 45), and the demographics and disease characteristics were balanced between the 2 groups. The addition of belinostat to paclitaxel/carboplatin did not improve PFS (group A, 5.4 months 95% confidence interval, 3.0‐6.0 months; group B, 5.3 months 95% confidence interval, 2.8‐6.6 months; P = .85). Overall survival was 12.4 months for group A versus 9.1 months for group B (P = .20). The response rate favored the belinostat group (45% vs 21%; P = .02). Belinostat resulted in a modest increase in treatment toxicity. CONCLUSIONS The addition of belinostat to paclitaxel/carboplatin did not improve the PFS of patients with CUP who were receiving first‐line therapy, although the patients who received belinostat had a higher investigator‐assessed response rate. Future trials in CUP should focus on specific subsets, defined either by the predicted tissue of origin or by the identification of targetable molecular abnormalities. Cancer 2015;121:1654–1661. © 2015 American Cancer Society. The addition of belinostat to combined paclitaxel and carboplatin does not improve the progression‐free survival of patients with carcinoma of unknown primary site who receive first‐line therapy, although patients who receive belinostat have a higher investigator‐assessed response rate.