Summary Background and aims The clinical value of synbiotics in patients receiving neoadjuvant chemotherapy currently remains unclear. The aim of this study was to investigate the effects of synbiotics in esophageal cancer patients receiving neoadjuvant chemotherapy on the intestinal microbiota and the adverse events of chemotherapy. Methods Sixty-one patients with advanced esophageal cancer who were scheduled to receive neoadjuvant chemotherapy were randomly allocated to 2 groups. One group received synbiotics during chemotherapy (n = 30), while the other group did not (n = 31). The fecal microbiota and organic acid concentrations were analyzed. The primary endpoint was the incidence of chemotherapy-related adverse events. Results The numbers of beneficial and harmful bacteria were significantly larger and smaller, respectively, in the synbiotics group than in the control group on day 10 of chemotherapy. The concentrations of acetic acid and propionic acid were significantly higher in the synbiotics group on day 10 of chemotherapy. The frequencies of severe lymphopenia and diarrhea were significantly less in the synbiotics group than in the control group (P = 0.033, 0.035, respectively). Furthermore, febrile neutropenia occurred less in the synbiotics group (10/30 in the synbiotics group vs 19/31 in the control group, P = 0.029). Conclusions Synbiotics during neoadjuvant chemotherapy in esophageal cancer patients reduced the occurrence of adverse events of chemotherapy through adjustments to the intestinal microbiota. (University Hospital Medical Information Network ( http://www.umin.ac.jp ), registration number UMIN000006875).