Background: Many techniques, methods and closure devices have been developed in order to reduce vascular complications that occur after coronary and peripheral interventions. The aim of the present study was to identify which method i.e. ultrasound (US) guidance or traditional access technique, is better for common femoral artery cannulation. Methods: The study included 939 patients, who were assigned to either the US-guided cannulation group (n = 449) or manual technique group (n = 490). The procedure time, first pass success rate, inadvertent venous puncture rate and complications developing within the first 7 days of the procedure were compared between the two groups. Results: No differences were found between the two groups regarding basic characteristics and antiplatelet and anticoagulant therapy administered during and up to 24 hours before the procedure. Arterial puncture attempts (p < 0.001), inadvertent venous entry (p = 0.02), and total procedure time (p = 0.012) were significantly lower in the US-guided group compared to the manual technique group. Furthermore, the first pass success rate was significantly higher in the US-guided group compared to the manual technique group (p < 0.001). The US-guided group had significantly lower pain levels (p < 0.001), hematomas (p < 0.001) and arteriovenous fistulas (p = 0.011) than the manual technique group. Conclusions: US-guided common femoral artery cannulation yields both higher access rates at first attempt and a shorter access time, and lower pain and complication rates.