Purpose The role of dobutamine during septic shock resuscitation is still controversial since most clinical studies have been uncontrolled and no physiological study has unequivocally demonstrated a beneficial effect on tissue perfusion. Our objective was to determine the potential benefits of dobutamine on hemodynamic, metabolic, peripheral, hepatosplanchnic and microcirculatory perfusion parameters during early septic shock resuscitation. Methods We designed a randomized, controlled, double-blind, crossover study comparing the effects of 2.5-h infusion of dobutamine (5 mcg/kg/min fixed-dose) or placebo in 20 septic shock patients with cardiac index ≥2.5 l/min/m 2 and hyperlactatemia. Primary outcome was sublingual perfused microvascular density. Results Despite an increasing cardiac index, heart rate and left ventricular ejection fraction, dobutamine had no effect on sublingual perfused vessel density 9.0 (7.9–10.1) vs. 9.1 n/mm (7.9–9.9); p  = 0.24 or microvascular flow index 2.1 (1.8–2.5) vs. 2.1 (1.9–2.5); p  = 0.73 compared to placebo. No differences between dobutamine and placebo were found for the lactate levels, mixed venous-arterial pCO 2 gradient, thenar muscle oxygen saturation, capillary refill time or gastric-to-arterial pCO 2 gradient. The indocyanine green plasma disappearance rate 14.4 (9.5–25.6) vs. 18.8 %/min (11.7–24.6); p  = 0.03 and the recovery slope of thenar muscle oxygen saturation after a vascular occlusion test 2.1 (1.1–3.1) vs. 2.5 %/s (1.2–3.4); p  = 0.01 were worse with dobutamine compared to placebo. Conclusions Dobutamine failed to improve sublingual microcirculatory, metabolic, hepatosplanchnic or peripheral perfusion parameters despite inducing a significant increase in systemic hemodynamic variables in septic shock patients without low cardiac output but with persistent hypoperfusion.