OBJECTIVE: To determine the effects of esmolol on hemodynamics and heart rate variability (HRV) in the early stage of sepsis. DESIGN: Prospective, randomized, controlled, parallel trial. SETTINGS: Veterinary research laboratory. ANIMALS: Ten anesthetized piglets. INTERVENTIONS: Septic shock was induced by infusing a suspension of live Pseudomonas aeruginosa IV in 10 anesthetized piglets. The piglets were resuscitated according to a standardized protocol using Ringer\'s lactate solution, norepinephrine, and milrinone. Once stabilized, the piglets were randomized to receive IV esmolol, titrated to a heart rate <90/min, or control, receiving saline. A pulmonary artery catheter and an arterial catheter were inserted for hemodynamic measurements. The Analgesia/Nociception Index (ANI) and the normalized HRV frequency domain parameters - high-frequency (HF), low frequency (LF), LF/HF ratio - were recorded using a proprietary monitor. MEASUREMENTS AND MAIN RESULTS: A significant decrease in cardiac output and heart rate, and a significant increase in systemic vascular resistance were observed over time in the esmolol group in comparison to the control group. No other differences were observed in hemodynamic parameters. No significant differences were observed in ANI variations or HRV parameters over time between groups. CONCLUSIONS: The administration of esmolol produced significant changes in hemodynamics with no change in ANI values or HRV parameters. Further study is needed to understand the effect of esmolol during sepsis.