Abstract: Objective A large-scale case-control study was conducted to evaluate the role of family history with nasopharyngeal carcinoma (NPC) and environmental factors (i.e. dietary, tobacco smoking and occupational exposures) in the development of NPC in Southern China. Both cases and controls are the participants for IgA antibodies to Epstein-Barr virus capsid antigens (EBV/IgA/VCA) positive. Methods The biopsy-confirmed NPC cases (n=1 010) and controls (n=1 009) who were NPC-free at the time of study enrollment came from Wuzhou City, Cangwu County and the neighboring Counties and cities of Wuzhou in Guangdong and Guangxi territory. Both of categories were defined as EBV/IgA/VCA positive. Univariate and multivariate unconditional logistic regression were used to analyze associations between the exposure factors and NPC. Results There was found that EBV/IgA/VCA positive individuals with a first-degree relative with NPC had 3.05 fold high risks to develop to NPC. Consumption of salted fish, wood fire and solvents exposure, starting smoking at an early age (<20 years) were significantly associated with increased risk of NPC. The OR value for each risk factor was 1.70, 4.04, 2.23 and 1.68 respectively. Conclusion The results that analysis was adjusted for EBV infection status confirmed that family history with NPC, consumption of salted fish, wood fire and solvents exposure, and smoking are still non-viral risk factors of NPC in Southern China.