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Tenascin-C (TNC) is involved in aortic disease pathophysiology. This study aims to evaluate TNC's value for predicting in-hospital death in acute aortic dissection (AD).We prospectively enrolled consecutive patients with suspected acute AD within 48 hours from symptom onset. Serum TNC and C-reactive protein (CRP) levels were examined on admission. Their baseline clinical characteristics and serum D-Dimer (DD) were collected. The endpoint was in-hospital death from AD.In the study cohort,78 survivors and 31 non-survivors with acute AD were enrolled. Compared to survivors, elevated median levels of serum TNC (141.10 pg/mL versus 75.30 pg/mL, P < 0.001), DD (8.74 μg/mL versus 4.58 μg/mL, P < 0.001), and CRP (19.20 mg/L versus 13.40 mg/L, P < 0.001) were found in non-survivors. Multiple logistic regressions revealed TNC, DD, and CRP were independent predictors of in-hospital death from acute AD. The OR and 95% CI were 1.038, 1.017-1.055; 1.084, 1.009-1.165 and 1.386, 1.107-1.643, respectively. Furthermore, TNC's sensitivity and specificity in predicting in-hospital death in acute AD were 83.87% and 83.33%. The combination of TNC and DD can improve the sensitivity and specificity to 90.30% and 88.46%.TNC is a valuable biomarker for predicting in-hospital death from acute AD. The combination of TNC and DD can improve predictions of in-hospital death from acute AD.