Objective: To compare the efficacy and impact on immune system of total laparoscopic and open distal radical gastrectomy with D2 dissection. Methods: The clinical data of patients with distal gastric carcinoma treated from 2009 to 2013 were retrospectively analyzed, and finally 78 cases were selected according to the inclusion and exclusion criteria. Of the patients, 38 cases underwent totally laparoscopic D2 radical gastrectomy (TLDG group), and 40 cases were operated with open distal D2 radical gastrectomy (ODG group). The parameters for efficacy and immune function between the two groups after the operation were compared. Results: In TLDG group compared with ODG group, the overall operative time (229.3 min vs. 197.7 min) and time for digestive tract reconstruction (27.6 min vs. 18.5 min) were significantly prolonged, but the intraoperative blood loss (99.5 mL vs. 175.3 mL), time to first postoperative flatus (3.6 d vs. 4.7 d), and theoretical postoperative discharge time (10.7 d vs. 14.7 d) were all significantly reduced (all P<0.05), while there was no statistical significance in the number of dissected lymph nodes, the distance of proximal margin, incidence of postoperative complications, follow-up rate, recurrence and metastasis rate, and 2-year survival rate between the two groups (all P>0.05); the white blood cell count, and IL-6 and CRP levels determined at postoperative day 1 and 7 were all significantly decreased (all P<0.05). Conclusion: Totally laparoscopic distal gastrectomy has the advantages of minimal invasiveness, less influence on immune function, and faster recovery. So it is a safe, feasible and effective procedure.