Head and neck cancer accounted for 3.3% of incident malignancies and 2.0% of cancer-deaths in the US in 2009, the majority of which are squamous in origin. Thus, there is a need for novel biomarkers for early detection and prognosis of squamous cell carcinoma of the head and neck (SCCHN). MicroRNA-137 plays a role in cell cycle control through negative regulation of Cdk6, and has been reported to undergo promoter methylation in oral squamous cell carcinoma. Oral rinse is a non-invasive mode of DNA collection, which may have some utility in detection of promoter methylation. The primary goals of this research were to determine if miR-137 promoter methylation occurs in all SCCHN, including pharyngeal and laryngeal tumors, and whether it is detectable in oral rinse samples; and to assess miR-137 promoter methylation as an etiologic and prognostic biomarker for SCCHN. DNA was extracted from oral rinses from 99 SCCHN patients and 99 cancer-free control subjects and from tumor tissue of 67 SCCHN patients; paired oral rinses and tumor tissue was available for 64 of the SCCHN patients. Promoter methylation status of miR-137 was determined by methylation-specific PCR. We identified a strong association between miR-137 promoter methylation detected in oral rinses and SCCHN (OR = 4.80, 95% CI: 1.23–18.82). There was a strong positive association between female gender and miR-137 promoter methylation in oral rinse from SCCHN patients (OR = 5.30, 95% CI: 1.20–23.44) and an inverse association with body mass index (OR = 0.88, 95% CI: 0.77–0.99). Promoter methylation of miR-137 in tumor tissue was associated with poorer overall survival (HR = 3.68, 95% CI: 1.01–13.38). In spite of its low sensitivity (21.2%), miR-137 methylation detected in oral rinse may have future value in methylation panels for early diagnosis of SCCHN due to its high specificity (97.0%) and occurrence in early stage disease; and its detection in tumor tissue has promise as a prognostic marker. The identification of novel diagnostic and prognostic biomarkers for SCCHN such as miR-137 promoter methylation will significantly impact public health through the reduction of morbidity and mortality that occurs as a result of this disease.