Background: PD-1/PD-L1 inhibitor monotherapy has been approved as second line therapy in advanced non-small-cell lung cancer (NSCLC). The study aims to compare clinical outcome of PD-1 inhibitor plus chemotherapy with PD-1/PD-L1 inhibitor monotherapy as 2nd/subsequent line therapy in advanced NSCLC. Methods: The clinical data of NSCLC patients who received PD-1/PD-L1 inhibitor as 2nd/subsequent line therapy were retrospectively collected in our study. According to the therapy modality, patients were assigned to PD-1/PD-L1 inhibitor monotherapy group and PD-1 inhibitor plus chemotherapy group. Disease control rates (DCRs), progression free survival (PFS) and overall survival (OS) were evaluated between the 2 groups. The prognostic role of derived neutrophils-to-lymphocyte ratio (dNLR) on the outcomes was also evaluated at the same time. Results: From April 2017 to October 2019, a total of 84 patients were enrolled in the current study. Twenty-six patients were allocated to the PD-1/PD-L1 inhibitor monotherapy group and fifty-eight patients were allocated to PD-1 inhibitor plus chemotherapy group. Chemotherapy regimens were detailed as follow: liposome paclitaxel (n = 15), nab-paclitaxel(n = 12), docetaxel(n = 9), pemetrexed(n = 6), and others(n = 16). Disease control rates (DCRs) and overall survival (OS) were not significantly different between the two groups. Progression free survival (PFS) in the PD-1/PD-L1 inhibitor monotherapy was longer(median PFS: NR vs 4.4 months, p = 0.02). Univariate and multivariate analyses suggested that derived neutrophils-to-lymphocyte ratio (dNLR) was independent prognostic factor of OS and gender was independent prognostic factor of PFS. In the second-line therapy subgroup of 38 patients, OS and PFS were not significantly different in the two groups. In the subgroup of 46 patients of over 2nd line, PD-1/PD-L1 inhibitor monotherapy group had longer PFS (median PFS: NR vs 4.0 months, p = 0.01).The incidence of any grade adverse events (AEs) was no significant difference in the two groups. One patient in the PD-1 inhibitor plus chemotherapy group died of immune-related pneumonitis. Conclusions: The addition of chemotherapy to PD-1 inhibitor as 2nd/subsequent line therapy had similar clinical outcomes compared with PD-1/PD-L1 inhibitor monotherapy of advanced NSCLC patients.