Background: Apoptosis plays an important role in origin of head and neck squamous cell carcinoma (HNSCC). Inherited genetic alterations, such as single nucleotide polymorphisms (SNPs), may influence the individual apoptotic capacity, having development of tumors as consequence. To the best of our knowledge, the roles of FASL c.-844C > T and FAS c.-671A > G SNPs in HNSCC risk, clinic pathological aspects, overall survival and progression free survival are unclear, and therefore these were the aims of our study. Methods: DNA of 463 patients and 470 controls were analyzed by PCR-RFLP. Patients were treated according to the Institutional protocol. The statistical analyses were realized using chi-square, logistic regression model, multifactor dimensionality reduction (MDR), Kaplan-Meier, and univariate and multivariate Cox analyses. Results:FASL TT genotype was more frequent in overall HNSCC patients (27.9% vs 16.2%, P = 0.001) and in those with SCC of oral cavity (30.0% vs 16.2%, P= 0.006), pharynx (29.9% vs 16.2%, P= 0.007), and larynx (25.4% vs 16.2%, P= 0.03) than in controls. Carriers of the genotypes were under a 3.24, 5.86, 2.93 and 2.54-fold increased risks of overall HNSCC and SCC of the mentioned subsites than others, respectively. An excess of FASL CT or TT plus FAS AA or AG combined genotype was seen in overall HNSCC patients compared to controls (91.1% vs 84.1%, P= 0.04); carriers of the genotype were under a 2.31-fold increased risk overall HNSCC than others. Among smokers, FASL TT and FAS AA genotypes were associated with 165.89 and 81.05-fold increased risks of HNSCC (P< 0.001), respectively. FASL c.-844C > T, FAS c.-671A > G SNPs and tobacco was the best interaction MDR model for risk of overall HNSCC and SCC of oral cavity, pharynx and larynx (P< 0.001). The median follow-up time of HNSCC patients was 46.0 months (1.6-166.0); no association of SNPs and patients´ survival was seen in study. Conclusions: Our data present preliminary evidence that inherited abnormalities in FASL c.-844C > T and FAS c.-671A > G SNPs are determinants of overall HNSCC and SCC of oral cavity, pharynx and larynx, particularly among smokers, possibly due to their action in tumor carcinogenesis.