Background Transmembrane (TMEM) proteins are involved in fundamental biological processes such as material transport and signal transduction. TMEM115 is a member of the TMEM protein family, but its significance in hepatocellular carcinoma (HCC) remains unclear. In this study, we investigate the clinical predictive significance and potential functions of TMEM115 in HCC. Methods Bioinformatics was used to investigate TMEM115 mRNA expression and immune infiltration score. Through multiplex immunohistochemistry analysis, we assessed its protein expression and association with HCC patient clinical features, prognosis and immune cell infiltration in HCC. Through in vitro and in vivo experiments, we evaluated the biological functions of TMEM115 in HCC cells and its impact on the immune microenvironment. Results TMEM115 mRNA and protein levels were significantly higher in HCC tissues compared to paracancerous liver tissues. Its protein expression correlated with clinical characteristics and overall survival in HCC patients. In HCC tissues, higher TMEM115 protein expression corresponded to lower proportions of CD66b+ neutrophils and CD8+ T cells and a higher proportion of CD4+ T cells. Furthermore, patients with low TMEM115 expression displayed higher programmed cell death ligand-1 and lower lymphocyte activation gene 3 protein expression. Functionally, TMEM115 knockdown inhibited the proliferation, migration and invasion of HCC cells. In orthotopic models, TMEM115 knockdown inhibited the growth of HCC and affected the infiltration of immune cells. Conclusions Our findings show TMEM115 as a promising prognostic indicator for HCC and hold promise in predicting responses to immune therapy, emphasising its potential clinical relevance and intricate involvement in the immune microenvironment of HCC.