Real-world safety and effectiveness data for trastuzumab plus chemotherapy treatment of human epidermal growth factor receptor 2 (HER2)-positive metastatic gastric cancer (mGC) patients in China are lacking. EVIDENCE was a prospective, multicenter, non-interventional registry study evaluating the safety and effectiveness of trastuzumab in five cohorts of Chinese GC patients, stratified by HER2 status and trastuzumab treatment. Effectiveness was analyzed for Cohorts I (HER2-positive, trastuzumab treated), II (HER2-positive, trastuzumab untreated), and IV (HER2-negative, trastuzumab untreated); trastuzumab-related adverse events (AEs) were analyzed for Cohort I. Cohorts I, II, and IV included 174, 113, and 422 patients, respectively. Most patients received first-line chemotherapy (87.6%). Median overall survival (OS1) for first-line treatment was 22.3, 17.2, and 17.4 months in Cohorts I, II, and IV, respectively. After excluding patients who had surgery, respective median OS1 was 19.9, 15.3 and 12.9 months. Respective first-line progression-free survival (PFS1) was 8.2, 6.9, and 6.2 months; and respective first-line response rates (RR) were 51.7%, 18.4%, and 32.8%. Cohort I was significantly favored over Cohort II for propensity score matched first-line median OS1 (hazard ratio [HR]: 0.61), PFS1 (HR: 0.64), and RR (odds ratio: 4.93). Trastuzumab-related AEs, grade 3-5 AEs, serious AEs, and AEs with a fatal outcome occurred in 23.6%, 3.4%, 2.3%, and 0.6% of Cohort I patients, respectively. Safety profiles were consistent with those known for trastuzumab and chemotherapy; trastuzumab treatment improved outcomes. Our study provides real-world data supporting first-line trastuzumab plus chemotherapy in Chinese HER2-positive mGC patients. NCT01839500 (ClinicalTrials.gov) IMPLICATIONS FOR PRACTICE: This prospective, non-interventional registry study aimed to provide safety and effectiveness data for the use of trastuzumab in combination with chemotherapy in Chinese patients with HER2-positive mGC from the real-world clinical setting. Trastuzumab plus first-line chemotherapy was shown to be safe and to improve outcomes when compared with patients treated with chemotherapy alone. Trastuzumab was effective within a range of treatment regimens; subgroup analysis showed that trastuzumab paired most effectively with the XELOX regimen. This study provides real-world clinical safety and effectiveness data supporting the use of trastuzumab in the treatment of Chinese patients with HER2-positive mGC. © AlphaMed Press 2021.