Objective To investigate the risk factors for major bleeding at femoral artery puncture sites during interventional treatment.Methods The clinical data of 879 patients who underwent femoral artery puncture were retrospectively analyzed, and according to the presence or absence of major bleeding, these patients were divided into major bleeding group (23 patients) and non-major bleeding group (856 patients). The clinical data were compared between the two groups, and the logistic regression equation was used to analyze the risk factors for major bleeding at femoral artery puncture sites.Results Of the 879 patients, 23 (2.6%) had the symptoms of major bleeding. The univariate analysis showed that in the major bleeding group and non-major bleeding group, the age (34.8% vs 7.9%), emergency treatment (26.1% vs 11.4%), serum creatinine, diabetes, compression time >4 hours (30.4% vs 9.7%), and high dose of the platelet membrane glycoprotein IIb/IIIa receptor antagonist tirofiban were associated with bleeding at femoral artery puncture sites. The multivariate regression analysis showed that age ≥74 years (median age), emergency treatment, diabetes, and high dose of the platelet membrane glycoprotein IIb/IIIa receptor antagonist tirofiban were closely associated with bleeding at femoral artery puncture sites (OR=2.187, 2.231, 1.485, 1.792, 0.742, and 2.741, P<0.05).Conclusions Age ≥74 years, emergency treatment, diabetes, and high dose of tirofiban are the high-risk factors for major bleeding at femoral artery puncture sites. Clinical intervention should be performed for such patients to reduce bleeding rate.