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Purpose: Microvascular invasion (MVI) impairs long-term prognosis of patients with hepatocellular carcinoma (HCC). We aimed to develop a novel nomogram to predict MVI and patients' prognosis based on radiomic features of contrast-enhanced CT (CECT)., Patients and Methods: HCC patients who underwent curative resection were enrolled. The radiomic features were extracted from the region of tumor, and the optimal MVI-related radiomic features were selected and applied to construct radiomic signature (Rad-score). The prediction models were created according to the logistic regression and evaluated. Biomarkers were analyzed via q-PCR from randomly selected HCC patients. Correlations between biomarkers and radiomic signature were analyzed., Results: A total of 421 HCC patients were enrolled. A total of 1962 radiomic features were extracted from the region of tumor, and the 11 optimal MVI-related radiomic features showed a favor predictive ability with area under the curves (AUCs) of 0.796 and 0.810 in training and validation cohorts, respectively. Aspartate aminotransferase (AST), tumor number, alpha-fetoprotein (AFP) level, and radiomics signature were independent risk factors of MVI. The four factors were integrated into the novel nomogram, named as CRM, with AUCs of 0.767 in training cohort and 0.793 in validation cohort for predicting MVI, best among radiomics signature alone and clinical model. The nomogram was well-calibrated with favorable clinical value demonstrated by decision curve analysis and can divide patients into high- or low-risk subgroups of recurrence and mortality. In addition, gene BCAT1, DTGCU2, DOCK3 were analyzed via q-PCR and serum AFP were identified as having significant association with radiomics signature., Conclusion: The novel nomogram demonstrated good performance in preoperatively predicting the probability of MVI, which might guide clinical decision., Competing Interests: The authors have no conflicts of interest for this work., (© 2022 Xu et al.)