Betel quid chewing, part of traditional Taiwanese culture, is common in 10%-20% of the human population worldwide. In this case-control study we assessed the independent and interactive role of habitual betel quid chewing and chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infection on risk of cirrhosis. Subjects enrolled included 210 pairs of sex- and age-matched cirrhotic patients and healthy controls. Information on risk factors was obtained through serologic examination of hepatitis B surface antigen (HBsAg) and antibodies to hepatitis C virus (anti-HCV), and a standardized personal interview with a structured questionnaire. Univariate analysis indicated that betel quid chewing, HBsAg+, anti-HCV+, alcohol drinking, and smoking are significant risk factors for cirrhosis. Multivariate analysis indicated that betel quid chewing (odds ratio [OR], 3.56), HBsAg (OR 20.37), and anti-HCV (OR 31.43) are independent risk factors for cirrhosis. Most betel quid chewers habitually drink alcohol. Although our analysis indicates that betel quid chewing acts independently from alcohol as a risk factor for cirrhosis, the confounding effect of alcohol cannot be excluded entirely by our study. There was an additive effect of the interaction between betel quid chewing and the presence of either HBsAg or anti-HCV. Moreover, a higher risk of cirrhosis was associated with longer duration of betel quid chewing and greater amount of betel quid consumed (each p for trend <0.0001). In conclusion, betel quid chewing appears to be an independent risk factor for cirrhosis. There is an additive interaction between betel quid chewing and chronic HBV/HCV infection.