The aim of this study was to investigate the associations of serum levels of neuron-specific enolase (NSE), pro-gastrin releasing peptide (ProGRP), and lactate dehydrogenase (LDH) with clinical response and survival in small cell lung cancer (SCLC) patients receiving first-line platinum-based chemotherapy.One hundred thirty-six patients with SCLC were recruited in this study. All the patients received first-line platinum-based chemotherapy. Clinical efficacy was assessed according to Response Evaluation Criteria in Solid Tumors v1.1 criteria. Serum samples were collected from SCLC patients before chemotherapy. NSE, ProGRP, and LDH levels were measured by commercial electrochemiluminescence immunoassay, enzyme-linked immune sorbent assay, and kinetic spectrophotometric method, respectively.Overall response rate was 71.3% with 97 patients who achieved complete response (CR) + partial response (PR). NSE and LDH level declined in patients who achieved CR + PR compared with patients in stable disease (SD) and progress disease (PD). Multivariate logistic regression analysis revealed that NSE > 50.324 ng/mL, stage ED, and distant metastases were independent risk factors for patients achieving CR + PR, and chemotherapy > 4 cycles was an independent protective factor in predicting CR + PR. Receiver operating characteristic (ROC) curves presented that expression of NSE, ProGRP, and LDH are of good predicting value for patients achieving CR + PR. Patients with a higher level of NSE and LDH presented worse progression-free survival and overall survival. In addition, multivariate Cox regression analysis showed that NSE level > 50.324 ng/mL and distant metastasis were independently correlated with worse OS.Serum NSE and LDH could be promising biomarkers for predicting therapy response and survival of SCLC patients receiving first-line platinum-based chemotherapy.