Background: In order to achieve better hemostasis of puncture holes in the femoral artery (FA) after an endovascular procedure, this study evaluated the effect and safety of manual compression (MC) with QuikClot Combat Gauze (QIC) and with mechanical compression (using a C-clamp) of the common access site, the FA, in patients with peripheral arterial occlusive disease (PAOD) combined with anterior femoral artery calcification (AFAC).Methods: We prospectively reviewed 100 patients receiving either MC with QIC or mechanical compression (control group) after endovascular intervention for PAOD plus AFAC from February 2014 to September 2018 in a single unit, which was assessed using computerized tomography angiography (CTA). Results:The mean time to completion of hemostasis was 30±0 minutes in the control group and 18±2.20 minutes in the QIC group (P<0.001). The time to ambulation of the QIC and control groups was 4.38±0.46 and 4.86±0.30 hours (P<0.001), respectively. Eight (16%) patients in the control group had hematoma, as compared with one patient (2%) in the QIC group (P=0.031), while sixteen (32%) patients in the control group had ecchymosis, as compared with four (8%) in the QIC group (P=0.005). Use of QIC and coronary artery disease (CAD) were identified as independent factors correlated with an increased risk of minor complications.Conclusions: QIC facilitated effective and safe hemostasis in patients with PAOD and AFAC.