Background: Oxidative stress is a complicated process, which was defined as an increase in prooxidants and decrease in antioxidants caused by various mechanisms, including inflammation and surgical trauma. The association between acute appendicitis and oxidative stress has been showed in previous studies. However, comparison of oxidative stress in laparoscopic or open appendectomy (OA) has not been established. Patients and Methods: Patients who were diagnosed as acute appendicitis between October 2012 and January 2013 were randomized to open (OA, n = 50) and laparoscopic appendectomy (LA, n = 50). Blood samples for oxidative stress markers (total oxidant status [TOS] and total antioxidant status [TAS]), C-reactive protein (CRP) and white blood cells (WBC's) were collected just before the surgery and 24 h after surgery. Results: There were no differences in preoperative values of WBC and CRP between LA and OA groups (P = 0.523 and 0.424), however, in postoperative 24(th) h, CRP was reduced in LA group (P = 0.031). There were no differences in preoperative levels of TOS, TAS, and oxidative stress index (OSI) between LA and OA groups. In the postoperative 24(th) h, TOS and OSI were found to be significantly higher in OA group when compared to LA group (P = 0.017 and 0.002) whereas no difference was detected in TAS level in the postoperative 24(th) h (P = 0.172). Conclusions: This double-blind, randomized clinical trial provides evidence that LA for uncomplicated appendicitis is associated with significantly lower oxidative stress compared with OA. Some of the advantages of LA may be attributed to the significant reduction of oxidative stress in these patients.