Abstract: Objective To explore the effectiveness and safety of tegafur combined with thalidomide in the maintenance treatment of human epidermal growth factor receptor-2 (Her-2) negative patients with advanced gastric cancer. Methods A total of 40 patients with Her-2 negative recurrent and metastatic gastric cancer were enrolled, who were admitted in Chizhou People's Hospital from January 2014 to December 2017 and underwent first-line chemotherapy for 4—6 cycles by SOX, XELOX or mFOLFOX6, with progression-free survival. The patients were randomly divided into two groups (n=20): a maintenance group and a control group. Patients in the maintenance group were orally administered with tegafur combined with thalidomide as the first-line chemotherapy, until progress of the disease or severe adverse reactions. The control group was simply followed up and symptomatically treated after the first-line anti-tumor drugs were discontinued. Both groups were compared for clinical effectiveness and adverse reactions. Results The maintenance group was more objective and effective than the control group (35.0% vs 0, P<0.05), with an increased disease control rate (75.5% vs 35.0%, P<0.05). The maintenance group showed significantly longer modified progression-free survival (mPFS, 8.25 months) than the control group (5.5 months) (P<0.05). The modified overall survival (mOS) of the two groups were 12.8 months and 11.7 months, without statistical difference (P>0.05). The maintenance group was characterized by Ⅰ-Ⅱ degree leukopenia, fatigue, liver function damage, while the adverse reactions were improved after symptomatic treatment, without toxic side effects and treatment related deaths. Conclusions After first-line chemotherapy of Her-2 negative and advanced gastric cancer, tegafur combined with thalidomide is effective in maintenance treatment, with accurate effectiveness, good tolerance, high safety and extended median PFS.