The aim of this prospective, double-blinded pilot trial study was to evaluate the effects of Thymosin alpha 1 use in the early phase on immunomodulation and clinical outcomes in patients with severe acute pancreatitis (SAP). A total of 24 patients with SAP were randomized to receive either conventional therapy for SAP or immunomodulatory therapy (TA1 group). The patients in the thymosin group were injected with Talpha1 3.2 mg twice per day for 7 days. The serum level of HLA-DR and CD4/CD8 ratio and other immune parameters were measured on admission, the 8th day and the 28th day. There was a low expression of monocyte HLA-DR in both groups on admission, and more rapid alterations in the HLA-DR were found in the TA1 group. The positive rates of blood and abdominal drainage culture were statistically significant during the 28th follow-up period. The duration of ICU stay was shorter after TA1 treatment. Improves cell-induced immunity and reduces infection rate in severe acute pancreatitis patients.