Abstract Introduction The objectives of this study were to determine the frequency and prognostic significance of beta-catenin expression in a cohort of non-small cell lung cancer (NSCLC) patients. Methods Tissue microarrays were constructed using clinically annotated formalin-fixed paraffin-embedded tumor samples from individuals diagnosed with NSCLC who underwent surgical resection with curative intent and had beta-catenin expression status determined by immunohistochemistry. Results Negative beta-catenin expression was seen in 28% (103/370) of NSCLC cases and was prognostic of a reduced overall patient survival ( P = .008) and also was significantly correlated with the presence of lymphatic invasion ( P = .015). In multivariate analysis, the loss of beta-catenin expression retained independent prognostic significance and showed an adjusted hazard ratio of 3.18 (confidence interval, 1.46-6.91, P = .004) for reduced patient survival when adjusting for the presence of lymphatic invasion, tumor grade, nodal status, and tumor stage. Conclusions Beta-catenin represents an important prognostic marker in individuals diagnosed with surgically resectable NSCLC.