The relationship of diabetes and smoking status to hepatocellular carcinoma (HCC) mortality is not clear. We aimed to investigate the association of smoking cessation relative to diabetes status with subsequent deaths from HCC.We followed up 51,164 participants (aged 44-94 years) without chronic hepatitis B or C from 1 January 1998 to 31 December 2008 enrolled from nationwide health screening units in a prospective cohort study. The primary outcomes were deaths from HCC.During the study period, there were 253 deaths from HCC. History of diabetes was associated with deaths from HCC for both total participants (adjusted hazard ratio [HR], 2.97; 95% confidence interval [CI], 2.08-4.23) and ever smokers with current or past smoking habits (HR, 1.92; 95% CI, 1.10-3.34). Both never smokers (HR, 0.46; 95% CI, 0.32-0.65) and quitters (HR, 0.62; 95% CI, 0.39-0.97) had a lower adjusted risk of HCC deaths compared with current smokers. Among all ever smokers with current or past smoking habits, as compared with diabetic smokers, only quitters without diabetes had a lower adjusted risk of HCC deaths (HR, 0.37; 95% CI, 0.18-0.78). However, quitters with diabetes were observed to have a similar risk of deaths from HCC when compared with smokers with diabetes. Regarding the interaction between diabetes and smoking status on adjusted HCC-related deaths, with the exception of quitters without history of diabetes, all groups had significantly higher HRs than nondiabetic never smokers. There was also a significant multiplicative interaction between diabetes and smoking status on risk of dying from HCC (P = 0.033). We suggest clinicians should promote diabetes prevention and never smoking to associate with reduced subsequent HCC mortality even in adults without chronic viral hepatitis.