Background: Serum tumor markers (STM) are viewed as surrogate indicators of tumor burden, and neutrophil-to-lymphocyte ratio (NLR) has been reported to be associated with the systematic inflammation and immunity status of the host. The present study was designed to evaluate early STM and NLR dynamics as combined biomarkers to predict efficacy and prognosis for advanced non-small cell lung cancer (NSCLC) patients who received immunotherapy with PD-1/PD-L1 inhibitors. Methods: We retrospectively reviewed patients with advanced NSCLC who were treated with PD-1/PD-L1 inhibitors. Several STM, including carcinoembryonic antigen (CEA), cytokeratin-19 fragments (CYFRA 21–1), neuron specific enolase (NSE), carbohydrate antigen 19–9 (CA19–9), and carbohydrate antigen 125 (CA125), and NLR were routinely measured or calculated at NSCLC diagnosis. Early leading STM and NLR change were evaluated between immunotherapy initiation and the first subsequent restaging. At least 20% decreases of the leading STM were considered as leading STM decrease after immunotherapy. Both pretreatment and posttreatment NLR < 5 were considered as continuous low NLR. A combination score based on the leading STM and NLR dynamics was calculated. The effects of leading STM change, NLR change, and the combination score on objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were analyzed in a training cohort (n = 79) and confirmed in a validation cohort (n = 35). Results: A total of 120 patients were included in this retrospective cohort study. The median age was 63.0 years and 71.0% was male. Overall, ORR was 20.0%, and median OS and PFS were 6.2 and 4.6 months, respectively. Patients with low combination score had a significantly improved ORR (15/60) compared to those with intermediate (0/11), or high score (0/4) (P = 0.032). In the training cohort, the combination score was significantly associated with OS (P< 0.001) and PFS (P< 0.001) for all patients, as well as for those with stable and progressive disease (P< 0.001 for OS; P< 0.001 for PFS). This combination score was also further confirmed to stratify patients with different prognosis in terms of OS (P< 0.001) and PFS (P< 0.001) in the validation cohort. In a multivariable model, the combination score was an independent indicator for predicting OS (P< 0.001) and PFS (P< 0.001). Conclusions: A simple and novel combination score based on early STM and NLR dynamics representing surrogate indicators of tumor burden, and immunity status, respectively, can accurately predict efficacy and prognosis for advanced NSCLC patients with PD-1/PD-L1 blockade.