Background and Aims Currently, the fenestration technique has been widely applied in the treatment of various thoracic aortic diseases. Fenestration techniques can be categorized into in situ fenestration and in vitro pre-fenestration, each with its own characteristics, advantages and disadvantages. This study was conducted to compare and analyze the short- and mid-term efficacy of in situ fenestration and in vitro pre-fenestration techniques in the reconstruction of left subclavian artery (LSA) for aortic arch lesions with unfavorable proximal landing zone (either short or unhealthy), and also summarize the experience in selecting fenestration approaches.Methods The clinical data of 215 patients with aortic arch diseases treated with LSA reconstruction using in situ fenestration or in vitro pre-fenestration technique in the First Affiliated Hospital of Zhengzhou University from March 2019 to March 2022 were retrospectively analyzed. Among them, 114 cases underwent in situ fenestration (in situ fenestration group), and 101 cases were treated with in vitro pre-fenestration (in vitro pre-fenestration group). The technical success rates, perioperative and follow-up adverse events, and mortality rates were compared between the two groups.Results The technical success rate in the in situ fenestration group was 93.9% (3 cases of fenestration failure, 3 cases of type Ia endoleak, and 1 case of access vessel injury); one patient developed bilateral multiple acute cerebral infarctions 4 d after operation, and the patient recovered well with conservative treatment; there were 3 aorta-related deaths within 30 d, with 2 deaths occurring on postoperative day 10 and day 25 due to visceral artery involvement causing multi-organ failure, and 1 death on postoperative day 2 due to rupture of the abdominal aorta dissection. The technical success rate in the in vitro pre-fenestration group was 94.1% (1 case of LSA coverage due to stent displacement, 3 cases of type Ⅲ endoleak, 2 cases of type Ia endoleak); one patient experienced right-sided acute cerebral infarction 1 d after operation and recovered well with medical treatment; there were no aorta-related deaths in this group. The median follow-up time was 26 (10-46) months in the in situ fenestration group and 19 (10-44) months in the in vitro pre-fenestration group. During the follow-up period, branch stent occlusion occurred in 1 case at 6 months after operation and type Ia endoleak occurred in 2 cases at 3 months in the in situ fenestration group; 1 case developed proximal dissecting aneurysm at 3 months after operation and 2 cases developed type Ia endoleak at 3 months after operation in the in vitro pre-fenestration group. There were no aorta-related deaths in either group. There were no statistically significant differences in technical success rates, perioperative and follow-up adverse event rates, and mortality rates between the two groups (all P>0.05).Conclusion Both in situ fenestration and in vitro pre-fenestration techniques for LSA reconstruction in the treatment of aortic arch diseases demonstrate good safety and efficacy. Individualized procedural selection based on patient anatomical conditions and disease characteristics can improve technical success rates and reduce complications.