Chemotherapy for squamous cell carcinoma with unknown primary (SCUP) has not been prospectively studied. To evaluate the efficacy of cis-diaminedichloroplatinum (cisplatin) and 5-fluorouracil (5-FU) in advanced SCUP, we treated 15 patients with measurable disease. A prospective trial was conducted of cisplatin and 5-FU in patients presenting with SCUP. All patients had evaluation in search for primary disease with computed tomographic scan of the head, neck, and chest and endoscopic evaluation of the nasopharynx, larynx, esophagus, and tracheobronchial passaes with negative blind biopsies. Chemotherapy consisted of cisplatin 100 mg/m2on day 1 and 5-FU 1000 mg/m2continuous infusion over 24 hr for 4 days. The regimen was repeated every 21 days. Responses were seen in 8 of 1.5 patients [1 complete response (CR) and 7 partial responses (PR)], for an overall response rate of 53%. These results suggest that cisplatin-5-FU combination has efficacy in advanced SCUP and deserves further trials both in advanced disease and in combined modality programs with surgery and radiation therapy.