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In recurrent or metastatic gastric cancer, second-line chemotherapy is generally recommended in current guidelines. Although third-line therapy is often performed in daily practice in some countries, there are only a few reports about its benefits.A retrospective review was conducted on 682 patients who underwent at least first-line chemotherapy for recurrent (n = 297) or primary metastatic (n = 385) disease. Clinicopathological characteristics and overall survival (OS) were analyzed according to lines of chemotherapy.One hundred sixty-seven patients (24.5%) underwent third- or further-line therapy. Third- or further-line therapy was frequently performed in patients with young age (<70) (P < .0001), Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1 (P < .0001), surgical resection before first-line therapy (P = .007), and first-line combination regimen (P = .001). The median OS for all patients after the initiation of first-line therapy was 10 months. The median OS of patients who received third- or further-line therapy was significantly longer than that of patients who received second- or lesser-line therapy (18 vs 8 months, P < .0001). The multivariate analysis revealed that third- or further-line therapy was independently associated with favorable OS (hazard ratio = 0.58, P < .0001). Moreover, patients who received third- or further-line therapy demonstrated better OS both in univariate (P = .002) and multivariate (P < .0001) analysis even after propensity score matching using baseline characteristics. The median OS after the start of third-line chemotherapy was 6 months. In addition, ECOG PS 0 or 1 at the initiation of third-line therapy (P < .0001) and surgical resection (P = .009) were independently associated with longer OS after third-line therapy.The current study suggests that third-line therapy could be recommended for recurrent or metastatic gastric cancer patients with good PS after progression from second-line chemotherapy in clinical practice.