No uniform consensus has been achieved regarding the ambulation protocol after transfemoral cerebral angiography (TFA). Until now, in most hospitals patients are prescribed 8-12 h strict immobilization along with bed rest in the supine position after TFA in China, which causes great discomfort to patients.To evaluate the effect of an evidence-based early ambulation protocol on the prevention of vascular complications and general discomfort in patients following transfemoral cerebral angiography (TFA).A prospective quasi-experimental study was conducted on 214 patients undergoing TFA with manual compression. Patients in the experimental group were placed supine position for 2 h with a sandbag placed on the wound dressing, followed by a semi-seated position for another 2 h. After this period, patients took 2 h bed rest (move freely) with the sandbag removed, and were allowed to get out of bed 6 h after TFA. Patients in the control group were restricted to an 8 h bed rest in a supine position with the affected leg straight and immobilized. The vascular complications (bleeding, hematoma, ecchymosis) and levels of comfort (low back pain, leg pain, and blood pressure) were evaluated after the procedure. Numeric Rating Scale (NRS) pain scores, systolic blood pressure (SBP); diastolic blood pressure (DBP) were measured hourly for 8 h after TFA.There was no significant difference in the two groups with regard to vascular complications including bleeding events (P = 0.621), bleeding volume (P = 0.321), and area of hematoma (P = 0.156). The area of ecchymosis in the experimental group was significantly smaller than the control group (P = 0.031). Compared with the control group, the NRS score for low back pain in the 4th, 5th, 6th, 7th, and 8th hour after TFA were significantly lower (P < 0.05), and the NRS score for leg pain in the 5th, 6th, 7th, 8th hour after TFA were significantly lower (P < 0.05). The SBP and DBP in the 6th, 7th, and 8th hour after TFA were significantly lower than the control group (all P < 0.05).The evidence-based early ambulation protocol can effectively and safely increase comfort and decrease the pain level for patients undergoing TFA, without change in the incidence of vascular complications.© 2024. The Author(s).