Objective: To compare the efficacy and safety of totally laparoscopic distal gastrectomy (TLDG) and laparoscopy-assisted distal gastrectomy (LADG) for gastric cancer. Methods: 104 patients with gastric cancer who underwent laparoscopic surgery were divided into TLDG group (n=48, TLDG) and LADG group (n=56, LADG) according to different surgical methods. The operation, postoperative general condition and postoperative complications were compared between the two groups, and the serum gastrointestinal hormones [gastrin (GAS), vasoactive intestinal peptide (VIP), motilin (MTL)] and inflammatory factors [C-reactive protein (CRP), interleukin-6 (IL-6)] were compared between the two groups before and after operation. Results: Compared with LADG group, TLDG group had less intraoperative blood loss (P<0.05), shorter main incision length (P<0.05), shorter first flatus time, ambulation time, first liquid diet time, drainage tube removal time and hospitalization time (P<0.05). There was no significant difference in the operation time and the number of lymph node dissection between the two groups (P>0.05). At 3 days after operation, the levels of serum GAS, VIP and MTL in TLDG group were higher than those in LADG group (P<0.05), and the levels of CRP and IL-6 were lower than those in LADG group (P<0.05). Conclusion: Compared with LADG, TLDG has more minimally invasive advantages in the treatment of gastric cancer, with small incision, less inflammatory stress, less impact on gastrointestinal hormones, faster postoperative recovery, and no increase in complications.