Objectives: Comparing the safety of transradial access (TRA) and conventional hemostasis with transfemoral access (TFA) and vascular closure devices (vessel plugs and suture devices) in patients undergoing percutaneous coronary interventions. Background: TRA for PCIs is associated with fewer bleeding and vascular complications compared with TFA. Vascular closure devices (VCD) are often used post TFA to establish early hemostasis and mitigate bleeding risk. However, the comparative efficacy of TRA and TFA with VCDs remains controversial. Method: Electronic database were systematically searched for all pertinent studies from inception through January 2020. Randomized studies, registry data, and abstracts published in peer-reviewed indexed journals were included. The short-term outcomes: major bleeding, vascular complications, and closure device failure were evaluated. Random-effects model was used to pool individual study results. Results: Twelve studies (8 observational, 4 randomized) including 7,961 patients (TRA: 3,121 patients, TFA and vessel plugs: 3,157 patients, TFA & suture devices: 1,683 patients) were included in the analysis. Major bleeding was significantly lower with TRA compared with TFA and vessel plugs (odds ratio [OR] 0.22, 95%CI 0.11-0.44, p < .00001) and TFA & suture devices (OR 0.12, 95%CI 0.05-0.28, p < .00001). Vascular complications were significantly lower with TRA compared to TFA and vessel plugs (OR 0.25, 95%CI 0.13-0.49, p < .0001) and TFA & suture devices (OR 0.13, 95%CI 0.04-0.41, p = 0.0005). Rates of closure device failure were lower for TRA compared to TFA & suture devices (OR 0.13, 95%CI 0.04-0.41, p = .0005), but similar to TFA & vessel plugs (OR 0.23, 95%CI 0.01-4.28, p = .33), although confidence intervals were wide. All analysis revealed a low to moderate level of heterogeneity.