Chronic graft-versus-host disease (cGVHD) is a frequent and potentially life-threatening complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Standard steroid first-line treatment could not satisfy therapeutic need due to its limited efficacy. SHR0302 is a highly selective Janus kinase (JAK) 1 inhibitor, which could alleviate symptoms and improve the survival of cGVHD mice in our preclinical study. We therefore conducted a phase I clinical trial to evaluate the safety and efficacy of SHR0302 plus prednisone as first-line treatment for moderate/severe cGVHD. A 3+3 design was implemented to define the optimal dose of SHR0302, which included five dose levels (1mg/2mg/4mg/6mg/8mg once a day). Meanwhile, prednisone was concurrently administrated with a dose of 1mg/kg/d and then gradually tapered after two weeks. The primary endpoint was safety, and the secondary endpoints were overall response rate (ORR) at day 28 and week 24. Eighteen patients were enrolled into the study. A maximum tolerated dose was not reached. All patients (100%) experienced adverse events (AEs), and 7 patients (38.89%) experienced grade≥3 AEs. No patient was discontinued treatment due to AEs. At week 4, the ORR and complete remission (CR) rates were 94.44% and 27.77%, while at week 24, were 82.35% and 64.71%, respectively. The event-free survival (EFS) at 24 months was 72.20% (95% CI, 51.40%-93.00%). In summary, SHR0302 in combination with prednisone had a high safety and could achieve a high response for naïve-treatment cGVHD, which suggest that SHR0302 combination might be an optimal choice for naïve-treatment cGVHD.