Unresectable head and neck squamous cell carcinoma (HNSCC), non-metastatic, comprises a heterogeneous group of patients (pts), formed of stage III and IV pts. Since the available literature had not distinguished among these two groups, we prospectively addressed whether the recommended regimen involving cisplatin 100 mg/m2 concurrent to conventionally delivered radiotherapy (RT) is feasible in stage IV pts, based on the efficacy and safety of this regimen. A total of 30 pts were enrolled onto this study. Chemoradiation (CRT) consisted of RT 70 Gy, delivered in 35 daily fractions of 2 Gy, in 7 weeks, concurrent to cisplatin 100 mg/m2 on days 1, 22 and 43. Supportive treatment was provided as needed. Twenty-eight pts had tumors staged as T4 and 20 had N2 or N3 cervical involvement. The most common primary sites were the oral cavity and the oropharynx (23 pts). We observed six complete responses and 12 partial responses, with an overall response rate of 60%. A high rate of treatment-related toxicities was observed, with three deaths during CRT, and 26 pts suffering from one or more grade 3/4 toxicities, mainly dysphagia, mucositis, dermatitis, vomiting, infection or anemia. A prolonged treatment time was observed (63 days), as a result of unplanned treatment breaks. The lack of requirement of red blood cell transfusion was favorably related to the response to the treatment (93% vs. 50%, P=0.033). For the whole population, with a median follow-up of 20.8 months, the median progression-free survival (PFS) was 8.0 months, and the median overall survival (OS) was 17.3 months. Longer median PFS and OS were seen in responding pts (12.8 vs. 4.1 months, P=0.0001; and not reached (NR) vs. 10.4 months, P=0.0037, respectively), as well as in those pts not requiring red blood cell transfusion (12.8 vs. 3.9 months, P=0.0162; and NR vs. 10.4 months, P=0.0176, respectively). In conclusion, this concurrent CRT regimen is hardly delivered in stage IV, unresectable, locally advanced HNSCC pts, due to treatment-related toxicities and longer RT duration. As a subset of pts may benefit from this regimen, adequate patient selection and aggressive supportive measures are essential.