The aim of the present study was to evaluate the efficacy and safety of a combination of intra-arterial and intravenous chemotherapy in the treatment of unresectable, advanced gastric cancer, and assess which patients are likely to benefit from combined treatment. The clinical data of 128 patients diagnosed with unresectable, advanced gastric cancer at The Fourth Hospital of Hebei Medical University (Shijiazhuang, China) from January 2009 to September 2012 were retrospectively analyzed. The patients were divided into two groups as follows: Those who received regional intra-arterial chemoembolization plus systemic chemotherapy (combined group; n=62) and those who received systemic chemotherapy only (venous group; n=66). The clinical response, overall survival (OS) and toxic effects in the two groups were compared. Univariate and multivariate analyses were performed to identify the primary factors affecting the survival time of patients in the combined group. The overall response rate was significantly increased (35.5%) in the combined group compared with the venous group (19.7%; P=0.045). The median OS was 14 months in the combined group and 13 months in the venous group, and the 1-year and 2-year survival rates in the two groups were 45.2 and 9.7%, and 40.9 and 6.1%, respectively. There were significant differences between the survival curves (P=0.044). The median time to progression in the combined group and the venous group was 10 months and 6 months, respectively, and the difference was statistically significant (P=0.003). Multivariate analysis revealed that tumor-node-metastasis (TNM)-stage and the degree of tumor staining were independent factors affecting OS. No differences in adverse reactions between the two groups were observed (P>0.05). The combination of intra-arterial and intravenous chemotherapy may effectively improve the rate of clinical response, prolong OS and time to symptomatic progression in patients with unresectable, advanced gastric cancer, in particular those with an earlier TNM stage and distinct tumor staining.