Background: Lung adenocarcinoma (LUAD) accounts for the majority of lung cancers, and the survival of patients with advanced LUAD is poor. The extracellular matrix (ECM) is a fundamental component of the tumor microenvironment (TME) that determines the oncogenesis and antitumor immunity of solid tumors. However, the prognostic value of extracellular matrix-related genes (ERGs) in LUAD remains unexplored. Therefore, this study is aimed to explore the prognostic value of ERGs in LUAD and establish a classification system to predict the survival of patients with LUAD. Methods: LUAD samples from The Cancer Genome Atlas (TCGA) and GSE37745 were used as discovery and validation cohorts, respectively. Prognostic ERGs were identified by univariate Cox analysis and used to construct a prognostic signature by Least Absolute Shrinkage and Selection Operator (LASSO) regression analysis. The extracellular matrix-related score (ECMRS) of each patient was calculated according to the prognostic signature and used to classify patients into high- and low-risk groups. The prognostic performance of the signature was evaluated using Kaplan-Meier curves, Cox regression analyses, and ROC curves. The relationship between ECMRS and tumor immunity was determined using stepwise analyses. A nomogram based on the signature was established for the convenience of use in the clinical practice. The prognostic genes were validated in multiple databases and clinical specimens by qRT-PCR. Results: A prognostic signature based on eight ERGs (FERMT1, CTSV, CPS1, ENTPD2, SERPINB5, ITGA8, ADAMTS8, and LYPD3) was constructed. Patients with higher ECMRS had poorer survival, lower immune scores, and higher tumor purity in both the discovery and validation cohorts. The predictive power of the signature was independent of the clinicopathological parameters, and the nomogram could also predict survival precisely. Conclusions: We constructed an ECM-related gene signature which can be used to predict survival and tumor immunity in patients with LUAD. This signature can serve as a novel prognostic indicator and therapeutic target in LUAD.Copyright © 2022 Xiao, Li, Huang, Fan, Qin, Liu and Yuan.