Retinol binding protein 4 (RBP4), as an adipokine, has been identified to be associated with several types of cancer. However, no studies have assessed its effect on non-small cell lung cancer (NSCLC) risk. The objective of this study was to assess the association between serum RBP4 levels and the risk of NSCLC. A case-control study design was used to recruit 256 confirmed NSCLC cases and 256 age- and gender-matched healthy controls by frequency between August 2017 and January 2019. Serum RBP4 was measured using enzyme-linked immune absorbent assay before treatment. Unconditional logistic regression analysis was applied to estimate the odds ratio and 95% confidence interval (CI). Serum RBP4 level was significantly higher in NSCLC patients than those in the healthy control group (36.05 +/- 8.28 vs 29.54 +/- 7.71 mu g/mL,P < .05). Higher serum RBP4 level was associated with increased risk of NSCLC (Ptrend = .001). Compare with those in the lowest tertile, the adjusted odds ratios were 1.85 (95% CIs 1.07-3.2) (P = .029) for the second tertile and 2.18 (95% CIs 1.37-3.45) (P = .001) for the highest tertile after adjusting for confounding variables. No interactions were observed after stratified analyses by body mass index and smoking status (Pfor interaction: .584 and .357). Our study indicated that serum RBP4 level was positively related to the risk of NSCLC. Additional studies with prospective design are required to confirm this finding.