Objectives: We aimed to evaluate the efficacy and safety of low-dose protamine in reducing access site-related complications during Transcatheter Aortic Valve Implantation (TAVI) as compared to full-dose protamine. Background: Access site-related complications represent an independent predictor of poor outcomes of TAVI. Data regarding heparin reversal with protamine and the dosage needed to prevent bleeding complications are scarce among patients undergoing TAVI. Methods: A total of 897 patients were retrospectively included in the study. Patients who underwent percutaneous coronary intervention within 4 weeks before or concomitantly with TAVI (n= 191) were given 0.5 mg protamine for each 100 units of unfractionated heparin. All other patients (n= 706) were considered as a control group and 1 mg protamine for each 100 units of heparin was administered. Results: The combined intra-hospital endpoint of death, life-threatening major bleeding, and major vascular complications were significantly more frequent in patients receiving low-dose protamine [29 (15.2%) vs. 50 (7.1%),p< 0.001]. After propensity matching (n= 130 for each group) for relevant clinical characteristics including anti-platelet therapy [19 (14.6%) vs. 6 (4.6%),p= 0.006], low-dose protamine predicted the combined endpoint (OR 3.54, 95%-CI 1.36–9.17,p= 0.009), and even in multivariable analysis, low-dose protamine continued to be a predictor of the combined endpoint in the matched model (OR 3.07, 95%-CI 1.17–8.08,p= 0.023) alongside baseline hemoglobin. Conclusions: In this propensity-matched retrospective analysis, a low-dose protamine regime is associated with a higher rate of major adverse events compared to a full-dose protamine regime following transfemoral TAVI.