Objectives: Thymosin alpha1 (Tα1) is considered a promising immunomodulatory drug. However, it is still unclear whether Tα1 should be recommended for the management of sepsis. Here we conducted a systematic review and meta-analysis to assess the efficacy of Tα1 based immunomodulatory therapy on the clinical outcomes of septic patients. Methods: We searched for relevant clinical trials published before Dec. 12, 2014 through electronic databases. All articles about Tα1 based immunomodulatory therapy for sepsis were included regardless of language. Two authors independently selected studies, extracted data and assessed the quality of each included study. We polled the data related to all-cause mortality with Review Manager 5.1. Results: Twelve controlled trials were evaluated in all. Tα1 based immunomodulatory therapy had a significant trend toward lower all-cause mortality among patients with sepsis (pooled risk ratio 0.68, 95%CI 0.59-0.78, p < 0.00001, 12 trials, n = 1480). Conclusions: Tα1 based immunomodulatory therapy was associated with a lower mortality in septic patients. Nevertheless, these findings should be interpreted cautiously because of the poor quality and small number of participants of the included trials. More well-designed worldwide multicenter clinical trials are needed to provide a conclusive guideline for clinical practice.