BACKGROUND: While the attributed risk factors for the vast majority of patients with squamous cell carcinoma of the head and neck (SCCHN) are smoking and alcohol abuse, there appears to be a rising proportion of SCCHN patients who report no significant smoking or drinking history. This study reports the demographic and potential risk factors of a large series of never smoker-never drinker (NSND) patients. METHODS: All subjects were participants in a prospective epidemiologic study of incident SCCHN. We obtained demographic data, clinical characteristics, and potential etiologic factors for 172 NSND patients and 1131 ever smoker-ever drinker (ESED) patients. RESULTS.: NSND patients were more likely to be female and to present at extremes of age, but overall were significantly younger than ESED patients. NSND patients had a higher proportion of oral cavity and oropharyngeal cancers than ESED patients had. Eleven percent of NSND patients (17% of NSND men) reported regular use of noncigarette tobacco products or marijuana, 41% (45% of NSND women) reported regular environmental exposure to tobacco smoke, 24% (36% of NSND men) reported regular occupational exposures to carcinogens/toxins, and 30% had a history of gastroesophageal reflux disease. More than half the NSND patients with an oropharyngeal primary were serologically positive for human papillomavirus type 16. CONCLUSION: NSND patients with SCCHN are commonly young women with oral tongue cancer, elderly women with gingival/buccal cancer, or young to middle-aged men with oropharyngeal cancer. While several exposures studied may be important to the etiology of a subset of these cancers in NSND patients, it is likely that no single known factor is responsible for a majority of SCCHN in NSNDs.