BACKGROUND Refractory septic shock in neonates is still associated with high mortality, necessitating an alternative therapy, despite all currently available treatments. This study aims to assess the vasopressor effect of methylene blue (MB) in comparison to terlipressin (TP) as adjuvant therapy for refractory septic shock in the preterm neonate. METHODS A double-blinded randomized controlled trial was conducted in the Neonatal Intensive Care Units at Ain Shams University, Egypt. Thirty preterm neonates with refractory septic shock were randomized to receive either MB or TP as an adjuvant to conventional therapy. Both MB and TP were administered as an intravenous loading dose followed by continuous intravenous infusion. The hemodynamic variables, functional echocardiographic variables, and oxidant stress marker were assessed over a 24 h period together with the side effects of MB. RESULTS MB causes significant improvement in mean arterial blood pressure with a significant decrease of the norepinephrine requirements (1.15±0.21μm/kg/min at baseline vs. 0.55±0.15μm/kg/min at 24 h). MB infusion causes an increase of the pulmonary pressure (44.73±8.53 mmHg at baseline vs. 47.27±7.91 mmHg after 24 h) without affecting the cardiac output. Serum malonaldehyde decreased from 5.45±1.30 nmol/mL at baseline to 4.40±0.90 nmol/mL at 24 h in the MB group. CONCLUSIONS Administration of MB to preterm infants with refractory septic shock showed rapid increases in systemic vascular resistance and arterial blood pressure with minimal side effects.