Background <p>Diminished levels of FXIII are significantly correlated with hematoma expansion (HE) and unfavorable clinical outcomes. Although the crucial function of FXIII in coagulation is well-recognized, the connection between FXIII deficiency and either HE or negative prognosis in patients with spontaneous intracerebral hemorrhage (sICH) is not well understood.</p> Methods <p>Patients with sICH were confirmed through baseline computed tomography scans conducted within 6 h of symptom onset. Plasma FXIII levels were assessed at the time of admission using a standardized enzyme-linked immunosorbent assay. Restricted cubic spline models were employed to explore potential nonlinear relationships between admission FXIII levels and both hematoma expansion and clinical outcomes. Multivariable logistic regression analyses were performed to ascertain the association between FXIII levels and functional outcomes at 3 months postonset.</p> Results <p>In the study cohort of 132 patients with sICH, 49 experienced HE. The median admission level of FXIII was significantly lower in patients with HE, with a median [IQR] of 8.21&#xa0;mg/L (6.33, 10.37), compared with those without HE, who had a median value [IQR] of 11.68&#xa0;mg/L (8.49, 21.20), <i>p</i> &lt; 0.001. A deficiency in Factor XIII, defined as a plasma level &lt; 10&#xa0;mg/L, was associated with HE, with a fivefold increase in risk as indicated by an adjusted odds ratio of 5 (95% CI 2.031–12.325; <i>p</i> &lt; 0.001). Furthermore, multivariable analysis revealed that this deficiency was associated with poor functional outcomes, defined as a modified Rankin Scale (mRS) score of &gt; 3, by a factor of 59.45 (OR 59.45, 95% CI 7.258–487.006; <i>p</i> &lt; 0.001), and increased the risk of mortality by a factor of 12.07 (OR 12.07, 95% CI 2.526–57.669; <i>p</i> = 0.002) in patients with sICH.</p> Conclusions <p>In a prospective observational cohort study of patients with sICH, FXIII deficiency was found to be associated with HE and poor prognosis.</p>