We evaluated whether the association between cigarette smoking and dementia risk is modified by genetic predisposition including apolipoprotein E (APOE) genotype and polygenic risk (excluding the APOE region). We included 193,198 UK Biobank participants aged 60-73 years without dementia at baseline. Of non-APOE-ε4 carriers, 0.89% (95% CI 0.73-1.08%) current smokers developed dementia compared with 0.49% (95% CI 0.44-0.55%) of never smokers (adjusted HR 1.78; 95% CI 1.39-2.29). In contrast, of one APOE-ε4 allele carriers, 1.69% (95% CI 1.31-2.12%) current smokers developed dementia compared with 1.40% (95% CI 1.25-1.55%) of never smokers (adjusted HR 1.06; 95% CI 0.77-1.45); of two APOE-ε4 alleles carriers, 4.90% (95% CI 2.92-7.61%) current smokers developed dementia compared with 3.87% (95% CI 3.11-4.74%) of never smokers (adjusted HR 0.94; 95% CI 0.49-1.79). Of participants with high polygenic risk, 1.77% (95% CI 1.35-2.27%) current smokers developed dementia compared with 1.05% (95% CI 0.91-1.21%) of never smokers (adjusted HR 1.63; 95% CI 1.16-2.28). A significant interaction was found between APOE genotype and smoking status (P = 0.002) while no significant interaction was identified between polygenic risk and smoking status (P = 0.25). APOE genotype but not polygenic risk modified the effect of smoking on dementia risk.