Extracorporeal hemoperfusion (EHP) may improve the course and outcomes of patients with septic shock by targeting cytokines or bacterial endotoxins (lipopolysaccharide [LPS]). Here, we present the results of a multicenter randomized controlled trial (clinicaltrials.gov/ct2/show/NCT04827407) to assess the efficiency and safety of Efferon LPS hemoperfusion cartridges engineered for multimodal targeting LPS, host-derived cytokine, and damage-associated molecule pattern molecules. Patients with intra-abdominal sepsis (IAS) and septic shock (Sepsis-3) were subjected to EHP procedures (n = 38). Control patients with IAS and septic shock (n = 20) were treated using conventional protocols without EHP. The primary end point was resolution of septic shock. Secondary end points included MAP, vasopressor drug dose, partial pressure of arterial oxygen/fraction of inspired oxygen ratio, Sequential Organ Failure Assessment score, length of stay in the intensive care unit, and satisfaction with device use by a 5-point Likert scale. Clinical laboratory tests for a blood cells count, lactate and creatinine concentration, nephelometry test for C-reactive protein, immunochemiluminescent test for procalcitonin, and immunoenzyme analysis for IL-6 concentration were used to monitor the EHP effect versus the control group. Data were analyzed followed the intentionto-treat approach. Wilcoxon STATA 16.0 (StataCorp, College Station, TX) and Excel 2019 with XLStat 2019 add-in (Addinsoft, Paris, France) were used for statistical analysis of the results. The Fine and Gray method of competing risks was used to analyze the primary end point and other data representing the time to event. EHP resulted in a significant and rapid increase in MAP and partial pressure arterial oxygen/fraction of inspired oxygen ratio, progressive decline in norepinephrine doses, and multiorgan deficiency, as evaluated by Sequential Organ Failure Assessment scores. Importantly, EHP led to significantly rapid cumulative mechanical ventilation weaning compared with the control group (subdistribution hazard ratio, 2.5; P = 0.037). Early 3-day mortality was significantly reduced in the Efferon LPS versus control group; however, no significant improvements in survival in 14 and 28 days were revealed. Laboratory tests showed rapidly decreased levels of LPS, procalcitonin, C-reactive protein, IL-6, creatinine, leukocytes, and neutrophils only in the Efferon LPS group. Results demonstrate that EHP with Efferon LPS is a safe procedure to abrogate septic shock and normalize clinical and pathogenically relevant biomarkers in patients with IAS.