Acute graft-versus-host disease (aGVHD) is a major life-threatening complication after allogeneic haematopoietic stem cell transplantation. Interleukin-27 receptor alpha (IL-27Rα) is a co-receptor of IL-27, an inflammatory cytokine that possesses extensive immunological functions. It has been reported that IL-27Rα can exist in its soluble form (sIL-27Rα) in human serum and can function as a natural IL-27 antagonist. In this study, we examined serum sIL-27Rα levels and evaluated their prognostic value in aGVHD. A total of 152 subjects were prospectively recruited and separated into the training group (n=72) and the validation group (n=80). Serum sIL-27Rα at neutrophil engraftment was measured by ELISA. In the training set, a cut-off value of sIL-27Rα=59.40ng/ml was identified to predict grade II-IV aGVHD (AUC=0.735, 95% CI 0.618-0.853, P=0.001). Cumulative incidences of grade II-IV aGVHD (P=0.004), relapse rate (P=0.008), and non-relapse mortality (P=0.008) in patients with low serum sIL-27Rα (≥59.40?ng/ml) were significantly higher than those of patients with high serum sIL-27Rα (<59.40ng/ml). Multivariate analysis confirmed that low sIL-27Rα level (HR=2.83 95% CI 1.29-6.19, P