We evaluated the efficacy and toxicity of cisplatin, tegafur plus uracil and leucovorin as neoadjuvant chemotherapy for locally advanced squamous cell carcinoma (SCC) of the oropharynx and hypopharynx. Forty-six patients (stage IV, 83%; N2/3, 52%) were treated with PUL (50 mg/m2 cisplatin on day 1, 300 mg/m2 tegafur plus uracil orally and 60 mg leucovorin orally on days 1-14) over a 14-day cycle. Evaluation after 3 cycles led to chemotherapy termination if primary tumor responses were less than partial responses. Otherwise, PUL was continued up to 6 cycles before locoregional therapy. Patients achieving at least good partial responses at the primary site after neoadjuvant chemotherapy received radiotherapy for organ preservation. Chemotherapy responses were analyzed by intent-to-treat. Response rates of primary sites were 71.7% (33 of 46) with 34.8% (16 of 46) showing a complete response. Thirty patients (65.2%) achieved good partial responses at the primary site. Overall response and complete response rates of neck lymph nodes were 68.6% (24 of 35) and 25.7% (nine of 35). The combined response rate of primary site and neck lymph nodes was 63% (95% confidence interval 48.5-77.5%) with a complete response rate of 15.2%. Toxicities of WHO grade 3-4 included anemia (19.6%), diarrhea (17.4%) and neutropenia (8.7%). With a median follow-up of 36 months, overall survival and disease-free survival rates were 45.7% (21 of 46) and 41.3% (19 of 46); organ preservation rate was 90% (19 of 21). We concluded that the outpatient PUL regimen was a moderately effective, less-toxic neoadjuvant chemotherapy for SCC of the oropharynx and hypopharynx. PUL should be studied further with other active agents or radiotherapy.