The soluble frizzled receptor protein (SFRP) family encodes antagonists of the WNT pathway, and silencing of these genes, through promoter hypermethylation, leads to constitutive WNT signaling. In bladder cancers, hypermethylation of the SFRP genes occurs more often in current and former smokers and is a strong predictor of poor patient survival. Hence, we examined methylation of these genes in another tobacco‐related epithelial cancer, head and neck squamous cell carcinoma (HNSCC), to determine if the pattern of tobacco exposure again predicts the epigenetic alteration of these genes. Using methylation‐specific PCR, the prevalence of methylation of SFRP1, SFRP2, SFRP4 and SFRP5 was 35, 32, 35 and 29%, respectively among 350 HNSCC cases. Promoter methylation of SFRP1 occurred more often in both heavy (OR 3.5, 95% CI 0.9–13.7) and light drinkers (OR 3.7, 95% CI 1.0–14.3) compared to nondrinkers. SFRP4 promoter methylation, on the other hand, occurred at a higher prevalence in never smokers and former smokers than in current smokers, and also was independently associated with HPV16 viral DNA. A joint effects model of SFRP4 promoter methylation demonstrated that smoking status and HPV virus significantly interacted (p < 0.04) such that never smokers with HPV16 had an OR of SFRP4 methylation of 9.0 (95% CI 2.1–38.6). These results suggest that epigenetic alterations of the SFRP genes are highly prevalent in HNSCC, and that the clonal selection for these alterations is complex and may be related to the carcinogenic exposures that are known risk factors for this disease. © 2006 Wiley‐Liss, Inc.