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Hepatocellular carcinoma (HCC) is a prevalent malignant digestive tumor. Numerous genetic mutations have been documented in HCC, yet the clinical significance of these mutations remains largely unexplored. The objective of this study is to ascertain the clinical value and biological effects of xin actin binding repeat containing 2 (<i>XIRP2</i>) mutation in HCC. The gene mutation landscape of HCC was examined using data from the Cancer Genome Atlas and the International Cancer Genome Consortium databases. The prognostic significance of the <i>XIRP2</i> mutation was assessed through KM plot analysis. The association between drug sensitivity and the <i>XIRP2</i> mutation was investigated using the TIDE algorithm and CCK-8 experiments. The biological effects of the <i>XIRP2</i> mutation were evaluated through qRT-PCR, protein stability experiments, and relevant biological experiments. The <i>XIRP2</i> mutation is one of the high-frequency mutations in HCC, and is associated with poor prognosis. A total of 72 differentially expressed genes (DEGs) were observed in HCC tissues with the <i>XIRP2</i> mutation as compared to those with the <i>XIRP2</i> wildtype, and these DEGs were closely related to ion metabolic processes. The <i>XIRP2</i> mutation was linked to alterations in the sensitivity of fludarabine, oxaliplatin, WEHI-539, and LCL-161. CCK-8 assays demonstrated that HCC cells carrying the <i>XIRP2</i> mutation exhibited increased resistance to fludarabine and oxaliplatin, but enhanced sensitivity to WEHI-539 and LCL-161 as compared with those HCC cells with the <i>XIRP2</i> wildtype. The <i>XIRP2</i> mutation was found to have no impact on the mRNA levels of XIRP2 in tissues and cells, but it did enhance the stability of the XIRP2 protein. Mechanically, the inhibition of <i>XIRP2</i> resulted in a significant increase in sensitivity to oxaliplatin through an elevation in zinc ions and a calcium ion overload. In conclusion, the <i>XIRP2</i> mutation holds potential as a biomarker for predicting the prognosis and drug sensitivity of HCC and serves as a therapeutic target to enhance the efficacy of oxaliplatin.