Lentinan (LNT) is a beta-glucan known to have a life-prolonging effect in combination with chemotherapy for patients with unresectable or recurrent gastric cancer. Thus, a multi-center trial of chemo-immunotherapy using S-1 combined with LNT may benefit patients with unresectable or recurrent gastric cancer with acceptable toxicity. With such a regimen, the median survival time in 32 patients was 559 days. Regardless of change to second-line chemotherapy, the mean period of using S-1+LNT for patients with long NC above 400 days was 725 days. In subset analyses, the survival period of the patients with G/L ratio of equal to or less than 2 was significantly better than that of the higher one (p<0.0001). The incidence of hematological toxicity (grade 3 leukopenia and thrombocytopenia) was 6.3% (2/32), and non-hematological toxicity (grade 2 dysgeusia) was 6.3% (2/32), while no grade 4 toxicity was observed. S-1 and LNT combination immunotherapy was carried out safely with high QOL and allowed a prolonged administration. S-1+LNT regimen may prolong NC periods in patients with unresectable or recurrent gastric cancer.