<p>Claudins are key components of tight junctions, essential for maintaining cellular adhesion, regulating intercellular molecule transport, and preserving cell polarity. Altered claudin expression can lead to tight junction dysfunction, potentially disrupting signaling pathways and contributing to the development of epithelial cancers. This study aims to explore the understudied role of CLDN18.2 in intrahepatic cholangiocarcinoma and its relationship with clinical outcomes. We analyzed tissue samples from 182 patients who underwent curative surgery for intrahepatic cholangiocarcinoma. Our research examined the relationship between CLDN18.2 expression and various clinical factors, including patient characteristics, pathological findings, and survival metrics such as overall survival (OS), disease-free survival (DFS), metastasis-free survival (MeFS), and local recurrence-free survival (LRFS). Overexpression of CLDN18.2 showed significant associations with R1 resection (<i>p</i> = 0.032) and advanced T stage (<i>p</i> = 0.043). Univariate analysis revealed that high CLDN18.2 expression was correlated with poorer OS (<i>p</i> = 0.0002), DFS (<i>p</i> &lt; 0.0001), LRFS (<i>p</i> &lt; 0.0001), and MeFS (<i>p</i> &lt; 0.0001). Multivariate analysis further confirmed that high CLDN18.2 expression was independently associated with worse OS (<i>p</i> = 0.015), DFS (<i>p</i> &lt; 0.001), LRFS (<i>p</i> &lt; 0.001), and MeFS (<i>p</i> &lt; 0.001). Overexpression of CLDN18.2 was associated with unfavorable clinical prognosis and adverse pathological features in intrahepatic cholangiocarcinoma. These findings suggest that CLDN18.2 could serve as a potential prognostic biomarker for intrahepatic cholangiocarcinoma.</p>