Background <p>Mex3a has been implicated in tumor progression in several malignancies; however, its clinical significance and biological role in hepatocellular carcinoma (HCC) remain incompletely understood.</p> Methods <p>Mex3a expression patterns and prognostic relevance were first explored using The Cancer Genome Atlas (TCGA) dataset. A single-institution cohort of 59 patients with HCC was then analyzed to evaluate the association between Mex3a expression and clinicopathological characteristics, overall survival (OS), and recurrence-free survival (RFS). Survival outcomes were assessed using Kaplan–Meier analysis and Cox proportional hazards regression. Functional assays in vitro and in vivo were performed to investigate the role of Mex3a in HCC progression.</p> Results <p>Mex3a was significantly upregulated in hepatocellular carcinoma tissues compared with non-tumor tissues in the TCGA cohort and was associated with poorer overall survival at the univariate level. In the clinical cohort, high Mex3a expression correlated with aggressive clinicopathological features. Multivariate Cox regression analysis demonstrated that Mex3a expression was an independent prognostic factor for overall survival after adjustment for established clinicopathological variables. In contrast, Mex3a expression was not independently associated with recurrence-free survival. Functional experiments revealed that Mex3a promoted malignant phenotypes of HCC cells in vitro and enhanced tumor progression in vivo.</p> Conclusions <p>Mex3a is associated with aggressive tumor behavior and serves as an independent prognostic factor for overall survival, but not recurrence-free survival, in patients with hepatocellular carcinoma. These findings suggest that Mex3a may contribute to disease progression and patient outcomes in HCC.</p>