Although programmed death 1 (PD-1) inhibitors are a standard second-line treatment for esophageal squamous cell carcinoma (ESCC), their efficacy when used in combination with chemotherapy or anti-angiogenesis targeted therapy is unclear. To compare the efficacy and safety of PD-1 inhibitor monotherapy with that of combination therapy. A retrospective study was conducted at the Shandong Cancer Hospital. Based on records, patients with advanced ESCC, treated with second-line or above PD-1 inhibitor-containing regimens from August 15, 2019 to April 12, 2021 were divided into combination (PD-1 inhibitors plus chemotherapy or anti-angiogenesis targeted therapy) and monotherapy groups. The primary endpoints were progression-free survival (PFS) and overall survival (OS). The baseline differences between subgroups were assessed using the χ2-test, Fisher's exact test, or Student's t-test. Follow-up period, PFS, OS, median survival, and 95% confidence intervals (CIs) were estimated using Kaplan‒Meier analysis. The log-rank test was used to compare subgroups. In the 169 patients included, clinical features were well balanced between both groups. The median PFS of the combination group was better than that of the monotherapy group (8.5 months [95%CI 6.3-10.7] vs. 3.2 months [95%CI 0.0-6.5]; hazard ratio (HR) = 0.34 [95%CI 0.13-0.92]; P < 0.001). The median OS showed the same trend (18.9 months [95%CI 14.4-23.3] vs. 9.8 months [95%CI 6.3-13.2]; HR = 0.47 [95%CI 0.21-1.04]; P = 0.010). Using PD-1 inhibitors in a combination treatment may improve PFS and OS, with acceptable toxicities.