[Objective] This study aims to reveal the expression of leucine-rich repeat-containing protein 59 (LRRC59) in Ewing sarcoma and its effect on the prognosis of patients. [Methods] Based on Gene expression data and clinical information of 56 Ewing sarcoma samples obtained from the International Cancer Genome Consortium (ICGC) database, Kaplan-Meier curve and univariate and multivariate Cox regression analysis were used to explore the relationship between LRRC59 expression and patient prognosis. The biological function of LRRC59 was further evaluated by Gene Ontology (GO) analysis. Connectivity Map (CMap) analysis screened drugs that might reverse the biological effects of LRRC59. Real-time quantitative polymerase chain reaction (RT-qPCR) was used to detect the expression level of LRRC59 mRNA in Ewing sarcoma cells [Results] The survival of patients in the high expression group of LRRC59 is shorter (P=0.010). High expression of LRRC59 as an independent risk factor predicts poor prognosis in patients with Ewing sarcoma (P<0.05). GO analysis showed that LRRC59 may be involved in regulating the formation of tumor cell focal adhesions and extracellular matrix. CMap analysis found that some drugs such as apigenin, quinostatin have potential therapeutic effects on Ewing sarcoma. RT-qPCR further verified that the expression of LRRC59 in Ewing sarcoma cells is higher than that in normal cells (P<0.001). [Conclusion] LRRC59 is an independent prognostic biomarker for Ewing sarcoma, which is expected to provide a novel therapeutic target for Ewing sarcoma.