Nivolumab monotherapy is the standardsecond-line treatment for advanced esophageal squamous cell carcinoma (ESCC)after failure of platinum-based chemotherapy without anti-PD-1 antibody. Fixed dosing with 240mg every 2weeks was approved initially, followed by fixed dosing with 480mg every 4weeks based on pharmacokinetics data. However, information on the comparative efficacy and safety of the two doses remains limited. We compared progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and the incidence of adverse events (AEs) between the two doses in 117 patients who received second-line (n = 85) or later-line (n = 32) nivolumab monotherapy at our institution between January 2016 and December 2021. In the second-line group, patient characteristics for the 240mg and 480mg groups were as follows (240mg vs. 480mg): performance status (PS) 0/1/2 was 34/61/5% vs. 54/42/4%, and prior fluoropyrimidine plus platinum therapy (FP) was 81.3% vs. 42.3%. In the later-line group, the characteristics were: PS 0/1/2 was 28/60/12% vs. 14/86/0%, and prior FP was 60.0% vs. 42.8%. ORR was 11.9 vs. 24.0% in the second-line group (p = 0.19) and 0 vs. 14.3% in the later-line group (p = 0.22). Median PFS was 1.7 vs. 4.1months on second-line (hazard ratio [HR] 0.60, 95% confidence interval [CI] 0.35-1.01, p = 0.056) and 1.4 vs. 1.8months on later-line (HR 0.58, 95% CI 0.23-1.46, p = 0.25); AEs of any grade were observed in 58.3 vs. 69.7%, respectively. The efficacy and safety of the two doses of nivolumab monotherapy were comparable in patients with advanced ESCC.