Sepsis, especially septic shock, and its complications have been linked to the hyperadrenergic stress response. Does decatecholaminization with dexmedetomidine (DEX) lower the in-hospital mortality in septic shock patients? This open-label randomized controlled trial assessed the effects of a heart rate (HR)-calibrated DEX infusion on in-hospital mortality in patients with septic shock and HR >90 beats per minute (bpm), whether they are mechanically ventilated or not. DEX was infused for 48 hours to maintain the HR at 60-90 bpm. Mechanically ventilated patients received conventional sedation in both groups. Other outcomes were the norepinephrine (NE) equivalent dose, the need for additional vasopressor, APACHE-II score, persistent atrial fibrillation (AF), and C-reactive protein (CRP). In 90 patients of either sex, DEX reduced the mean HR over the first three days in the ICU by 11.2 bpm (95% CI -17 to -5) (P < 0.001). The in-hospital mortality risk ratio (RR) was 0.68, 95% CI 0.43 to 1.07, P = 0.091. The DEX group received an NE equivalent dose of 0.55 (0.37-0.82) mcg/kg/min vs. 0.61 (0.47-0.89) (P = 0.121). DEX reduced the epinephrine infusion rescue: relative risk reduction = 0.6 (95% CI 0.06 to 0.93), P = 0.025. The RR of persistent AF was 0.47; 95% CI 0.21 to 0.99; P = 0.05. DEX reduced the median APACHE-II score on the third day by -6; 95% CI -10 to -2; P =0.003; and the mean CRP concentration by -40 mg/dl (95% CI of -78 to -3.4, P = 0.033). The study was underpowered to detect a reduction in in-hospital mortality or NE equivalent dose in septic shock patients with DEX. However, DEX might reduce epinephrine infusion rescue, persistent AF, the APACHE-II score, and CRP.