Protein-bound polysaccharide K (PSK) is an anticancer agent used for adjuvant therapy against gastric cancer. The aim of this study was to evaluate the effect of PSK on the overall survival of patients with gastric cancer. A total of 254 patients who underwent surgical curative resection were included in this retrospective study. We identified 138 patients who received antimetabolites alone (control group) and 115 patients who received antimetabolites plus PSK (PSK group). In patients with early tumor recurrence, overall survival was significantly better in the PSK group (p=0.023). In patients with pN3 lymph node metastasis, median overall survival was better in the PSK group compared with the control group (p=0.032). Our results suggest that adjuvant immunochemotherapy with PSK increased the overall survival for patients with pN3 and early tumor recurrence. Thus, the combination of PSK with oral chemotherapeutic agents might be suitable for postoperative adjuvant therapy against gastric cancer in patients with lymph node metastases.