The feasibility and safety of coronary angiography (CAG) and angioplasty via trans-snuffbox approach (TSA) is still concerned; therefore, in this study, we aimed to assess possible complications occurring after TSA versus trans-radial approach (TRA). This prospective observational study was undertaken from June 2017 till March 2018. Individuals aged at least 18 years who were admitted for CAG through upper extremity were eligible and categorized to TSA (n = 70) and TRA (n = 56) groups. Occurrence of complications including hematoma, pain or paresthesia, pseudoaneurysm formation, arterial obstruction, limb ischemia, and major adverse cardiovascular events (MACE) including death, myocardial infarction (MI), stroke, and emergency vessel revascularization was assessed after the procedure and in two separate visits three and six months afterwards. The mean age of participants in TSA and TRA groups was 55.1 ± 9.7 and 56.5 ± 9.6 years, respectively (P = 0.415). Men were the dominant group in both approaches [TSA: 44 (62.8%), TRA: 36 (64.3%), P = 0.868]. Success rates in TSA and TRA were 88.6% and 94.6%, respectively (P = 0.230). Radial artery occlusion (RAO) was reported in two (3.2%) and one (1.8%) case in TRA and TSA, respectively (P = 0.653). MACE incidence was not significantly different in TSA compared with TRA group (1.8% vs. 4.8%, respectively, P = 0.389). There was no major procedural complication, neither in TSA nor in TRA category. Our results revealed that TSA could be classified as an alternative modality to other common CAG and angioplasty methods due to its high safety rate and lower complications. Several comprehensive population-based studies are necessary for confirming these findings. © 2020 Isfahan Cardiovascular Research Center & Isfahan University of Medical Sciences.