BACKGROUND Refractory septic shock (RSS) requiring major vasopressor support is associated with high mortality, especially in Gram-negative infections. The study aim was to describe hemodynamics, organ failure, and clinical outcomes in high-dose vasopressor therapy (HDVT) RSS patients treated with Polymyxin B hemoperfusion (PMX-HP) as rescue therapy. METHODS We retrospectively analyzed 52 patients, unresponsive to conventional therapy, treated with two sessions of PMX-HP requiring HDVT (norepinephrine and/or epinephrine requirement (NEP+EP) ≥ 0.5 µg/kg/min), ≥ 2 organ failures, and suspected/confirmed Gram-negative infection from any source. RESULTS At baseline, mean arterial pressure (MAP) was 80 ± 13 mmHg and NEP + EP requirement was 1.11 ± 0.56 µg/kg/min. After two PMX-HP sessions, at 72 h, MAP significantly increased and NEP + EP requirement decreased respectively by 12% and 76%. Pulmonary and renal function also improved significantly. Thirty patients (58%) showed a ≥ 50% reduction in NEP + EP dose within only 24 h after the first PMX-HP session (early responders), and 22 did not or died from irreversible shock in the same time frame (early non-responders). The 30-day hospital mortality was 29%; it was 16% in early responders and 45% in early non-responders. On multivariate analysis, SAPS II score, vasopressin, and central venous pressure significantly affected 30-day hospital mortality. CONCLUSIONS This is the first study describing the use of PMX-HP as a rescue therapy in RSS patients with HDVT and MOF. Our results suggest a possible role for PMX-HP in improving hemodynamics, organ function, and mortality in RSS, with a 30-day survival of up to 70%.