Background <p>Desmosine exerts a vital role as a cross-linking molecule integrate into a three-dimensional elastin network. After degradation of mature elastin, desmosine is released and enters into the circulatory system. The purpose was to estimate the association between serum desmosine level and Coronavirus disease 2019 (COVID-19) patients.</p> Methods <p>All 333 COVID-19 patients were enrolled and regarded as the training cohort, and 150 cases were used for completely independent validation cohort. Serum specimens were collected on the day of admission. The level of serum desmosine was determined by enzyme-linked immunosorbent assay (ELISA).</p> Results <p>Serum desmosine level on the day of admission gradually increased with elevating severity scores among COVID-19 patients. Spearman correlation analysis unveiled the close relationships between serum desmosine level and clinical parameters, such as liver function, renal function, myocardial enzymes, and inflammatory cytokines. The training cohort and external validation cohort revealed that serum desmosine level was positively associated with severity scores by multivariable linear regression analyses. Multivariable logistic regression models found that higher serum desmosine concentration on admission elevated the risks of mechanical ventilation, vasoactive agent use, ICU admission, and death during hospitalization. A receiver operating characteristic (ROC) curve analysis demonstrated the excellent discrimination for the poor prognosis of serum desmosine concentration by the training set and validation set.</p> Conclusions <p>Baseline serum desmosine level was positively associated with disease severity scores and worse clinical outcomes among COVID-19 patients during hospitalization, substantializing that serum desmosine might serve as a biomarker for discriminating the severity and prognosis in COVID-19 patients.</p>