Objective: To explore the short-term clinical efficacy of retroperitoneal laparoscopic surgery versus open surgery on giant pheochromocytoma, and provide a reference for clinical treatment. Methods: Seventy patients with giant pheochromocytoma who were admitted to our hospital from January 2012 to January 2017 were enrolled. The patients were divided into an observation group (n=35) and a control group (n=35) by random number table method. The observation group was treated with laparoscopic surgery and the control group was given open surgery. The therapeutic effects of the 2 groups were compared. The changes of plasma cortisol and quality of life scores were compared before and after surgery. The incidence of complications during the treatment was compared with the 2 groups. Results: After treatment, the total effective rate of the observation group (97.14%) was higher than the total effective rate of the control group (85.71%), but the difference was not statistically significant (P>0.05). The intraoperative blood loss/postoperative pain score of the observation group was lower than that of the control group (P<0.05). The recovery time of gastrointestinal function, postoperative extubation time, and postoperative hospital stay of the observation group was shorter than that of the control group (P<0.05). The levels of plasma cortisol decreased in the two groups after operation, but the observation group was higher than the control group (P<0.05). There was no difference in plasma cortisol expression between the observation group and the postoperative group (P>0.05). After operation, the quality of life, physical function, and mental function of the two groups were increased, and the observation group was higher than the control group (P<0.05). During the treatment period, both groups had tachycardia, hypotension, infection, and other complications. The total incidence of the observation group was 8.57%, which was significantly lower than the total incidence of complications in the control group (28.57%, P<0.05). Conclusion: Laparoscopic surgery has less damage to the body, less bleeding during the operation, reduces the pain of patients, promotes the recovery of gastrointestinal function after operation, has little effect on plasma cortisol level, reduces the length of patient hospitalization, improves patient quality of life, and has a high safety profile, which is worthy of clinical promotion and use.