The aim of this study was to determine the risk factors for the mortality during the first 30 days after a major head and neck cancer surgery. Two hundred and sixty one consecutive surgical procedure were prospectively studied at Oscar Lambret Cancer Centre within a 36-months period. Twenty variables were recorded for each patient. The significant risk factors for postoperative mortality were assessed by univariate and multivariate analysis. Overall 30-days mortality rate was 3.83% [95% CI 3.13-4.53]. In univariate analysis identified four risk factors: female gender (odd ratio 4.25 [95% CI 1.03-17.56]), age equal or superior than 70 (odd ratio 5.06 [95% CI 1.35-18.36]), current alcohol addiction (odd ratio 3.65 [1.02-13.06]) and laryngeal location (odd ratio 4.23 [CI 95% 1.18-3.38]). In multivariate analysis only female gender and laryngeal location remained significant. The incidence of postoperative mortality was 1.63% for patients without risk factor and was 6.41% for those with one or two risk factors. This model identifies easily high-risk patients for major head and neck cancer surgery. A multicenter validation is necessary.