Background: Due to the pivotal role of inflammatory cytokines in sepsis, hemoperfusion with cytokine adsorbents may lead to better outcomes. Although previous studies showed inconclusive results, proper patient selection and timing of hemoperfusion may lead to improved survival. Objectives: To examine whether patients with septic shock requiring high-dose vasopressors undergoing add-on hemoperfusion with a cytokine adsorbent have better clinical outcomes than those treated with standard treatment alone. Methods: This is a multi-center, randomized controlled study in 2 tertiary care centers. 206 patients with septic shock receiving norepinephrine of 0.2 mcg/kg/min or higher are randomized to receive either standard treatment combined with 3-hour sessions of hemoperfusion with cytokine adsorbent for two consecutive days (HP group) or standard treatment alone (ST group). The primary outcome is 28-day mortality. Secondary outcomes include hospital and ICU mortality, shock reversal, vasoactive-inotropic score (VIS), organ support-free days, interleukin-6 levels, as well as safety data. Conclusions: This study will provide information to guide the use of hemoperfusion with a cytokine adsorbent in patients with septic shock.