It is critical to find fast and robust biomarkers for sepsis to reduce the patient's risk for morbidity and mortality. In this work, we compared serum protein expression levels of regenerating islet-derived protein 3 gamma (REG3A) between patients with sepsis and healthy controls and found that serum REG3A protein was significantly elevated in patients with sepsis. In addition, expression level of serum REG3A protein was markedly correlated with the Sequential Organ Failure Assessment score, Acute Physiology and Chronic Health Evaluation II score, and C‐reactive protein levels of patients with sepsis. Serum REG3A protein expression level was also confirmed to have good diagnostic value to differentiate patients with sepsis from healthy controls. Finally, serum REG3A protein expression level was found to have good prognostic value to predict the 28-day survival rate of patients with sepsis. In conclusion, our work indicated that serum REG3A may be a novel biomarker for sepsis.