Recurrent head and neck squamous cell carcinoma (HNSCC) continues to have a high incidence. Staging and pathological grading are helpful, but imperfect predictors of recurrence. Accordingly, molecular biomarkers that predict the risk of recurrence need to be identified to improve clinical outcomes. We used a quantitative methylation-specific PCR (Q-MSP) assay to define patterns of DNA methylation that delineate the behavior of primary tumors and to detect micrometastases in clinically negative lymph nodes. The promoter methylation statuses of the promoters of 11 tumor-related genes (p16, RASSF1A, E-cadherin, H-cadherin, MGMT, DAPK, DCC, COL1A2, TAC1, SST, and GALR1) were analyzed in 133 HNSCC cases using Q-MSP. We detected frequent methylation of p16 (44%), RASSF1A (18%), E-cadherin (53%), H-cadherin (35%), MGMT (35%), DAPK (53%), DCC (42%), COL1A2 (44%), TAC1 (61%), SST (64%), and GALR1 (44%) in HNSCC. Disease-free survival was lower in patients with a high number of methylated genes (6–11) than in those with a low number of methylated genes (0–5) (log-rank test, P = 0.001). In a multivariate logistic-regression analysis, methylation of E-cadherin, COL1A2, TAC1, and GALR1 was associated with poor survival, with hazard ratios of 4.975 (95% CI, 1.537–16.098). In a joint analysis of these four genes, patients with 2–4 methylated genes had a significantly lower survival rate than those with 0–1 methylated genes in early-stage HNSCC.In conclusion, we demonstrated that the methylation profiles of 11 TRGs are valuable biomarkers for the prognosis of HNSCC. Furthermore, the methylation profiles of E-cadherin, COL1A2, TAC1, and GALR1 were the most powerful combination for predicting early-stage HNSCC. This demonstrates that molecular stratification may predict cancer progression. The application of the current findings can benefit HNSCC screening and surveillance algorithms. Although our study was retrospective, was conducted at a single institution, and the number of patients was small, it serves as a platform to establish optimal therapeutic strategies for early-stage HNSCC.