Background Abnormalities in the intrinsic apoptosis pathway, associated with single nucleotide variants (SNVs) in caspase (CASP) genes, alter head and neck squamous cell carcinoma (HNSCC) proliferation and progression. This prospective study aimed to evaluate whether CASP9 c.‐1339A>G and CASP3 c.‐1191A>G SNVs influence the outcome of patients with HNSCC. Two hundred sixty‐two HNSCC patients were enrolled in the study. Methods DNA and RNA of peripheral blood samples were analyzed using real‐time polymerase chain reaction (PCR) for genotyping and quantitative PCR method for gene expression, respectively. Differences in CASP3 expressions were analyzed using the Mann‐Whitney test. Event‐free survival (EFS) and overall survival (OS) were calculated using the Kaplan‐Meier curves, log‐rank test, and Cox analyses. Results CASP3 c.‐1191AG or GG genotype was associated with higher CASP3 expression when compared with AA genotype (0.50 arbitrary units (AUs) ± 0.29 standard deviation (SD) vs 0.28 AUs ± 0.12 SD; P = .02). Patients with CASP9 c.‐1339GG genotype had 1.54 more chance of presenting disease progression or relapse than patients with CASP9 c.‐1339AA or AG genotype. Patients with CASP9 c.‐1339GG and CASP3 c.‐1191GG combined genotype had 2.64 more chance of presenting progression or relapse of the disease and 2.84 more chance of evolving to death than those with the remaining combined genotypes. Conclusions Our findings provide, for the first time, preliminary evidence that inherited abnormalities in the intrinsic apoptosis pathway, related to CASP9 c.‐1339A>G and CASP3 c.‐1191A>G SNVs, act as predictors of HNSCC patients' survival.