AIM: Nivolumab, approved for adjuvant therapy in resected esophageal cancer, is typically administered at 240 mg every 2 weeks (Q2W) or 480 mg every 4 weeks (Q4W). However, data on the 480 mg Q4W regimen as an initial therapy are limited. In this study, we evaluated its safety and efficacy. METHODS: This prospective cohort study included 50 patients with pathologically confirmed lymph node metastases who underwent radical esophagectomy following preoperative therapy. All patients received at least one dose of nivolumab (480 mg Q4W). The primary endpoint was the incidence of Grade 3 or higher nivolumab-related adverse events (AEs). RESULTS: Of the cohort, 88% (44/50) received preoperative chemotherapy. The pathological lymph node status was distributed as follows: ypN1 (42%), ypN2 (40%), and ypN3 (18%). A total of 26 patients (52%) completed one year of therapy. Therapy discontinuation occurred because of relapse (30%), nivolumab-related AEs (10%), or patient preference (8%). Nivolumab-related AEs occurred in 70% of the patients, with Grade 3 or higher AEs occurring in 8%. The most common AEs were skin-related reactions (30%), elevated aspartate aminotransferase levels (24%), fatigue (12%), hypothyroidism (12%), and hyperthyroidism (10%). The majority of AEs occurred during the first four cycles, whereas thyroid dysfunction, arthritis, and pulmonary AEs appeared even later. One- and two-year disease-free survival (DFS) rates were 78.0% and 52.2%, respectively. Patients aged < 65 years and those with ypN2 disease demonstrated better DFS. CONCLUSION: Adjuvant nivolumab 480 mg Q4W may represent a potential treatment option with a manageable safety profile and favorable short-term DFS.