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Objective: To investigate whether esmolol could improve clinical outcome and tissue oxygen metabolism by controlling heart rate (HR) in patients with septic shock., Methods: A single-center double-blinded randomized controlled trial was conducted. The patients suffering from septic shock received 6-hour early goal directed herapy (EGDT) with pulmonary artery wedge pressure ≥ 12 mmHg (1 mmHg = 0.133 kPa) or central venous pressure CVP) ≥ 12 mmHg requiring norepinephrine to maintain mean arterial pressure (MAP) ≥ 65 mmHg and HR ≥ 95 bpm admitted to intensive care unit (ICU) of Guangdong General Hospital from September 2013 to September 2014 were enrolled. They were randomly divided into esmolol group and control group by computer-based random number generator. All patients received conventional basic treatment, while those in the esmolol group received in addition persistent esmolol infusion by micro pump with dosage of 0.05 mg · kg(-1) · min(-1) with the dosage adjusted to maintain HR lower than 100 bpm within 24 hours. The patients in control group did not receive drug intervention for HR. The primary end-points consisted of length of stay in ICU and 28-day mortality. The secondary end-points included hemodynamic parameters [HR, MAP, CVP, cardiac index (CI), stroke volume index (SVI), systemic vascular resistance index (SVRI)] and tissue oxygen metabolism parameters [central venous oxygen saturation (ScvO2), lactate level (Lac)] before and 24, 48, 72 hours after the treatment., Results: A total of 48 patients with septic shock were enrolled with 24 patients in esmolol group and 24 in control group. (1) The primary end-points: compared with control group, the length of stay in the ICU in the esmolol group was significantly shortened (days: 13.75 ± 8.68 vs. 21.70 ± 6.06, t = 3.680, P = 0.001), and 28-day mortality was significantly lowered [25.0% (6/24) vs. 62.5% (15/24 ), χ2 = 6.857, P = 0.009]. (2) The secondary end-points: there were no significant difference in the hemodynamic and tissue metabolism parameters before treatment between two groups. No significant difference was found between before and after treatment of all above parameters in control group. HR and Lac in the esmolol group were obviously declined, SVI, SVRI, SCvO2 were gradually increased, but no significant difference in MAP, CVP, and CI was found. Compared with the control group, HR in the esomolol group was significantly lowered (bpm: 84.4 ± 3.5 vs. 111.2 ± 7.2, P < 0.01), SVRI and ScvO2 were significantly increased from 24 hours [SVRI (kPa · s · L(-1) ·m(-2)): 137.9 ± 1.6 vs. 126.9 ± 1.3, ScvO2: 0.652 ± 0.017 vs. 0.620 ± 0.017, both P < 0.01]; SVI was significantly increased (mL/m2: 39.9 ± 2.2 vs. 36.8 ± 1.7, P < 0.01) and Lac level significantly declined from 48 hours (mmol/L: 2.8 ± 0.3 vs. 3.4 ± 0.3, P < 0.01)., Conclusion: The results demonstrate that HR controlled by a titrated esmolol infusion given to septic shock patients was associated with an improvement in tissue metabolism, reduction in the length of ICU stay and lowering of 28-day mortality.