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Background Accumulating evidence has shown that long noncoding RNA (lncRNA) CRNDE functions as an oncogene in many cancer types. However, its clinical value has not yet been explored in hepatocellular carcinoma (HCC). Methods A total of 166 patients with HCC and 100 healthy volunteers were enrolled in this study. The expression levels of serum exosomal lncRNA CRNDE were detected in patients with HCC and controls by quantitative real‐time PCR (qRT‐PCR). Results The serum exosomal lncRNA CRNDE expression levels were significantly increased in patients with HCC compared with normal controls. High serum exosomal lncRNA CRNDE expression was significantly associated with tumor size, tumor differentiation, and TNM stage. Receiver operating characteristic (ROC) analysis revealed that an area under the ROC curve (AUC) of 0.839, with a sensitivity and specificity of 69.3% and 85.0%. In addition, the overall survival (OS) and disease‐free survival (DFS) were significantly longer in patients with lower serum exosomal lncRNA CRNDE expression compared to those with higher CRNDE expression. Moreover, HCC patients with cirrhosis had worse OS and DFS than those without cirrhosis. Univariate and multivariate analyses indicated that high serum exosomal lncRNA CRNDE expression was an independent indicator of poor prognosis. Conclusion Taken together, serum exosomal lncRNA CRNDE might serve as a potential biomarker for HCC diagnosis and prognosis.