Background. Sini Decoction (SND) is composed of Aconitum carmichaelii Debeaux, Zingiber officinale Roscoe, and Glycyrrhiza uralensis Fisch, having been used in China for centuries for collapsing phrase of disease. Studies reported that SND could alleviate inflammatory response, ameliorate microcirculatory disturbances, and improve shock reversal and adrenal gland glucocorticoid stress response during sepsis shock, yet the underlying mechanism is still elusive. Toll-like receptor (TLR) 4 is demonstrated to be crucially correlated with the corticosterone secretion and the impaired adrenal glucocorticoid responses in sepsis. Materials and Methods. SND at dose of 10 g/kg (in low-dose SND group, LD-SND) and 20 g/kg (in high-dose SND group, HD-SND) was administered to CLP rats. Four days later, overall survival rates of rats were calculated; rat serumand adrenal glands were collected. Basic serum corticosterone levels were determined, and the increase of corticosterone after 0.8 ug/kg ACTH injection was checked to detect the adrenocortical sensitivity to ACTH. The protein and mRNA expression of TLR4 in adrenal glands were measured to study the impact of SND on TLR4 expression. mRNA levels of IL-10 and TNF-a in adrenal glands and IL-10 and TNF-a levels in serum were also determined to study the cytokines profile. Results. SND improved the cumulative survival rate of CLP rats up to 4 days (P < 0.05 with HD-SND) and adrenocortical sensitivity to 0.8 ug/kg ACTH stimulation (P < 0.05 at 60 mins, 31.02 +/- 19.23 ng/ml in LD-SND group and 32.18 +/- 14.88 ng/ml in HD-SND group versus 5.03 +/- 13.34 ng/ml in CLP group), with a significant decrease of protein (P < 0.05, 29.6% in LD-SND group and 27.8% in HD-SND group), mRNA expression of TLR4 (P < 0.05, 32.9% in LD-SND group and 36.1% in HD-SND group), mRNA expression of IL-10 (P < 0.05, 32.0% in LD-SND group and 29.6% in HD-SND group), TNF-a in adrenal glands (P < 0.05, 26.0% in LD-SND group and 25.3% in HD-SND group), and TNF-a level in serum (P < 0.05, 100.20 +/- 19.41 pg/ml in LD-SND group and 92.40 +/- 11.66 pg/ml in HD-SND group versus 134.40 +/- 27.87 pg/ml in CLP group). Conclusion. SND increased overall survival rate within 4 days and attenuated adrenal insufficiency in septic rats by downregulating TLR4 mRNA and protein expression in adrenal tissue, inhibiting adrenal production of TNF-alpha and IL-10, and improving adrenal responsiveness. Our results suggest that SND is able to ameliorate adrenal stress responses in a local immuneadrenal crosstalk way involving downregulated expression of TLR4 in adrenal tissue. SND might be a promising treatment for adrenal insufficiency prevention in prolonged sepsis.