Background: Apatinib, a VEGFR-2 tyrosine kinase inhibitor, is wildly used for the treatment of advanced or metastatic gastric cancer. However, dose modification and interruption are happened frequently due to poor patient conditions and treatment-related toxicity. This study was designed to explore the efficacy and safety of intermittent or continuous apatinib therapy in combination with docetaxel. Methods: This was an open-label, randomized clinical trial. Patients with advanced gastric cancer who progressed from first-line treatment were randomly assigned in a ratio of 1:1 to receive intermittent or continuous dosing schedule. In the intermittent dose group (IG), patients received oral apatinib 500 mg/d for 5 days followed by 2 days off. In the continuous dose group (CG), patients received 500 mg daily without interruption. Docetaxel 60 mg/m² was administered intravenously to patients on Day 1 in a 21-day cycle in both groups. The primary endpoint was progression-free survival (PFS). The secondary endpoints included overall response rate (ORR), disease control rate (DCR), overall survival (OS), and the safety. Results: Between September 15, 2017 and November 30, 2020, 80 patients were screened for eligibility, of which 76 patients were randomly assigned into two groups (38 in the IG and 38 in the CG). In the IG and CG, 38 and 37 patients had ECOG PS 0-1, 16 and 19 patients had history of surgery, both 11 patients with more than 2 metastases, respectively. The baseline characteristics of the two groups were balanced. ORR in the IG was 21.05% vs 18.42% in the CG, and DCR was 60.53% vs 60.53%, respectively. Median PFS were 3.88 months (95% CI, 1.723-6.031) vs 3.98 months (95% CI, 1.055-6.896, p= 0.546), and median OS was 9 months (95% CI, 5.306-12.698) vs 9.40 months (95% CI, 5.204-13.588, p= 0.310) in two groups. The incidence of all grade adverse events (AEs) in the IG and CG were 94.7% and 92.1%, of which the most common AEs were hypertension (55.3% vs 65.8%), anemia (55.3% vs 63.2%), proteinuria (26.3% vs 31.6%), hand-foot syndrome (21.1% vs 26.3%). The incidence of grade ≥3 AEs were 36.8% and 39.5% in the IG and CG, respectively. In addition, the doses of 7 patients were reduced to the 250 mg in the IG, while that of 13 patients in the CG. Conclusions: Apatinib administered intermittently (5 days on/ 2 days off) exhibited similar efficacy to continuous schedule, while with less toxicity. Intermittent dosing schedule of apatinib may be an option for second-line treatment of patients with advanced gastric cancer. Clinical trial information: NCT03334591