BACKGROUND: Apatinib is a systemic therapeutic agent for advanced gastric adenocarcinoma (GAC) and gastroesophageal junction adenocarcinoma (GEJA). Its efficacy can be enhanced by applying it as a combination therapy, but the evidence supporting its combination application as a second-line treatment is not well documented. In the current study, we aimed to assess the efficacy and safety profile of apatinib, both as a monotherapy and in combination regimens, for second-line treatment of GAC and GEJA in real-world settings. METHODS: In this retrospective cohort analysis, we analyzed clinical data from 96 patients with advanced GAC or GEJA who received second-line apatinib monotherapy or combination therapy. Cox regression analysis was performed to identify prognostic factors influencing clinical outcomes of different treatment approaches (apatinib combination with other drugs). RESULTS: The results indicated that the overall objective response rate (ORR) and disease control rate (DCR) for second-line apatinib therapy were 19.8% and 31.3%, respectively. The median progression-free survival (mPFS) was 4.8 months (95% CI: 4.3-6.2m), while the median overall survival (mOS) was 10.3 months (95% CI: 8.9-12.4m). Multivariable Cox regression analysis identified gender, liver metastasis, and peritoneal metastasis as independent predictors of inferior PFS and OS outcomes. In terms of safety, the primary adverse reactions included myelosuppression, elevated AST and ALT levels, hypertension, hand-foot syndrome, hyperbilirubinemia, proteinuria, fatigue, and vomiting, with a low incidence of grade 3-4 toxicities. CONCLUSIONS: Apatinib-based combination therapy significantly enhances both progression-free survival and overall survival in patients with advanced gastric cancer when compared to monotherapy, while also demonstrating a safe and reliable profile.