The aim of this study was to investigate the prognostic value of galanin (GAL) and galanin receptor (GALR) promoter hypermethylation in patients with head and neck squamous cell carcinoma (HNSCC). The methylation status of three genes-GAL, GALR1, and GALR2 was examined in HNSCC patient tumors using quantitative methylation-specific PCR (Q-MSP). To determine the prognostic value of GAL, GALR1 and GALR2 methylation status, their associations with various clinical characteristics and patient survival were assessed in HNSCC patient tumors (n = 142). Aberrant methylation of at least one gene was observed in 84 of the 142 (59.2 %) primary tumors analyzed. The methylation index, defined as the ratio between the number of methylated genes and the number of genes examined, was positively correlated with larger tumor size (P = 0.034) and disease recurrence (P < 0.001). In the multivariate logistic-regression analysis, methylation of both GAL and GALR1 exhibited the highest association with poor survival (hazard ratio, 6.83, P = 0.002). Moreover, among patients without lymph node metastasis, a multivariate analysis showed a significant trend for poor survival as the number of hypermethylated genes increased (log-rank test, P = 0.003). CpG hypermethylation is a likely mechanism of GAL and GALR1/2 gene inactivation, indicating that GAL and its receptors play a role in HNSCC tumorigenesis. As such, GAL and GALR1/2 methylation status may serve as an important biomarker for clinical outcome.