Streptozocin (STZ) administration with or without other cytotoxic drugs remains a crucial chemotherapy for patients with advanced pancreatic neuroendocrine neoplasms (Pan-NENs). However, the therapeutic effects of combination treatment with weekly STZ and oral S-1 therapy (STS1) remain unknown. Therefore, the aim of this study was to evaluate the safety and clinical feasibility of STS1.Twenty of 243 Pan-NEN patients were included in this retrospective study, all of whom had received STS1 for unresectable or distant metastatic diseases from November 2015 to January 2019. The maximum tumor shrinkage rate, time course of the tumor shrinkage rate, prognosis (progression-free survival and overall survival), and adverse events were evaluated.The median age of the patients was 61.5 years and the median tumor size was 35 mm. The number of NET-G1, NET-G2, NET-G3, and NEC-G3 patients was 3, 13, 3, and 1, respectively. The median Ki-67 index and mitoses were 10.2% and 2/10 high-power fields, respectively. The overall objective response rate and disease control rate were 30% and 90%, respectively. The median maximum tumor reduction rate was 19%. The Ki-67 index and tumor size did not influence the tumor shrinkage rate. Progression-free survival after STS1 treatment was 19 months with no significant difference between NET-G1/G2 and NET-G3/NEC-G3 patients (p = 0.4). There was one case each of grade 3/4 toxicity, including general fatigue, hyperglycemia, and renal dysfunction. No serious myelosuppressive events are manifested.STS1 treatment is an effective and safe therapeutic option for patients with advanced Pan-NEN.