Systemic inflammation response syndrome (SIRS) is a key and mainly detrimental process in the pathophysiology of multiple organ dysfunction syndrome. The balance of pro-inflammation and anti-inflammation controls the initiation and development of SIRS. However, the endogenous counterregulatory immune mechanisms that are involved in the development of SIRS are not well understood. CD4+CD25+Foxp3 (forkhead box P3)+ regulatory T lymphocytes (Treg cells) play a key role in the immunological balance of the body. Thus, our aim was to investigate the contribution of these key immunomodulators (Treg cells) to the immune dysfunction that is observed in zymosan-induced SIRS in mice. We first evaluated the level of Treg cells in the lung of mice 6 h, 1 d, 2 d, 3 d, 5 d, and 7 d after the injection of zymosan or normal saline by western blot, real-time PCR and flow cytometry. We found that the number of Treg cells and the levels of the Treg cell-related transcription factor (Foxp3) and cytokines (IL-10) in the zymosan-treated group significantly decreased on day 1 and day 2 and significantly increased on day 5 compared with the NS-treated group. In the next experiment, the mice were injected with 200 μg of anti-CD25 mAb (clone PC61) to deplete the Treg cells and then injected with zymosan 2 days later. The number of Treg cells decreased by more than 50% after the injection of the PC61 mAb. In addition, the expression of the anti-inflammatory cytokine IL-10 also decreased. Moreover, the depletion of the Treg cells profoundly increased the mice'mortality and the degree of lung tissue injury. In conclusion, Treg cells tend to play a protective role in pathogenesis of the zymosan-induced generalized inflammation, and IL-10 signaling is associated with their immunomodulatory effect.