Background: Periprocedural stroke is a rare but life-threatening complication of percutaneous coronary intervention (PCI). Transradial intervention (TRI) is more beneficial than transfemoral intervention for periprocedural bleeding and acute kidney injuries, but its effect on periprocedural stroke has not been fully investigated. Our study aimed to assess risk predictors of periprocedural stroke according to PCI access site. Methods and Results: Between 2008 and 2016, 17 966 patients undergoing PCI were registered in a prospective multicenter database. Periprocedural stroke was defined as loss of neurological function caused by an ischemic or hemorrhagic event with residual symptoms lasting at least 24 hours after onset. Periprocedural stroke was observed in 42 patients (0.3%). Stroke patients were older and had a higher incidence of chronic kidney disease, peripheral artery disease, and acute coronary syndrome but were less likely to undergo TRI. Multivariable logistic regression analysis revealed TRI (odds ratio; 0.33; 95% CI, 0.16–0.71; P =0.004) was significantly associated with a lower occurrence of periprocedural stroke. Finally, propensity score–matching analysis showed that TRI was associated with a reduced risk of periprocedural stroke compared with transfemoral intervention (0.1% versus 0.4%; P =0.014). According to our sensitivity analysis, this finding was robust to the presence of an unmeasured confounder in almost all plausible scenarios. Conclusions: TRI was associated with a reduced risk of periprocedural stroke compared with transfemoral intervention. Increased TRI use may reduce overall PCI complications and should be recommended as the optimal access site for both urgent/emergent and elective PCIs.