Background: To compare definitive radiochemotherapy with weekly administration of 30-40 mg/m2 of cisplatin to 100 mg/m2 of cisplatin on days 1, 22 and 43 for outcomes and toxicity in patients with squamous cell carcinoma of the head-and-neck. Methods: Seventy-five patients receiving radiochemotherapy with weekly cisplatin (30-40 mg/m2) were compared to 58 patients receiving radiochemotherapy with 100 mg/m2 cisplatin on days 1, 22 and 43. Radiochemotherapy regimen plus seven characteristics (age, gender, performance score, tumor site, T-/N-category, histologic grading) were evaluated for locoregional control (LRC), metastases-free survival (MFS) and overall survival (OS). Radiochemotherapy groups were compared for toxicity. Results: On multivariate analysis, improved LRC was associated with cisplatin 100 mg/m2 (hazard ratio [HR] 1.57; p = 0.008) and female gender (HR 4.37; p = 0.003). Radiochemotherapy regimen was not significantly associated with MFS on univariate analysis (p = 0.66). On multivariate analysis, better MFS was associated with ECOG performance score 0-1 (HR 5.63; p < 0.001) and histological grade 1-2 (HR 1.81; p = 0.002). On multivariate analysis, improved OS was associated with cisplatin 100 mg/m2 (HR 1.33; p = 0.023), ECOG performance score 0-1 (HR 2.15; p = 0.029) and female gender (HR 1.98; p = 0.026). Cisplatin 100 mg/m2 was associated with higher rates of grade ≥3 hematotoxicity (p = 0.004), grade ≥2 renal failure (p = 0.004) and pneumonia/sepsis (p = 0.033). Conclusions: Radiochemotherapy with 100 mg/m2 of cisplatin every 3 weeks resulted in better LRC and OS than weekly doses of 30-40 mg/m2. Given the limitations of a retrospective study, 100 mg/m2 of cisplatin appears preferable. Since this regimen was associated with considerable acute toxicity, patients require close monitoring.