Nasopharyngeal cancer (NPC) is a major public health problem in parts of Southeast Asia and North Africa, but is rare among whites and blacks. Although infection with the EBV and genetic susceptibility appear to play large roles in high-incidence populations, migrant studies suggest that environmental factors may also be important. Aside from the high risks associated with ingestion of salted fish, surprisingly few other risk factors have been established from studies in endemic areas. We studied a low-incidence population to determine whether tobacco use, alcohol consumption, and certain medical conditions and treatments are related to NPC and to examine variations in risk by histology. We reasoned that new relationships might be best identified in the absence of strong causal pathways, such as intake of preserved foods and genetic susceptibility. A population-based case-control study was conducted from 1987 to 1993 at five cancer registries in the United States: western Washington, metropolitan Detroit, Connecticut, Iowa, and Utah. Controls were identified by random digit dialing and frequency matched to the gender and age distribution of cases at each registry. Telephone interviews were completed by 231 cases and 246 controls. We observed a strong dose-response relationship between cigarette smoking and risk of differentiated squamous cell carcinoma (test for trend, P < .001). The highest risk [odds ratio (OR), 6.5; 95% confidence interval (CI), 2.0-21.3] occurred among current smokers with a history of more than 60 pack-years. In contrast, there was no evidence that undifferentiated or nonkeratinizing carcinomas were associated with cigarette smoking. Similarly, a significant increase in risk was observed for the heaviest alcohol consumers (21 or more drinks/week) only for differentiated squamous cell carcinomas (OR, 2.9; 95% CI, 1.2-6.9). The associations with cigarettes and alcohol appeared to be stronger among persons 50 years or older. There was a suggestion that diagnosis with infectious mononucleosis (a marker of late infection with EBV) is linked with decreased NPC risk (OR, 0.4; 95% CI, 0.1-1.1). This report indicates that over two-thirds of differentiated squamous cell NPC cases arising in older persons in the United States can be accounted for by cigarettes and alcohol, but leaves unexplained cases arising in the young and carcinomas of undifferentiated or nonkeratinizing histology. Future studies of NPC need to take into account histology and age in evaluating these and other environmental and genetic risk factors.