Background: We describe a combinatorial intensive care approach and discuss the critical factors that allowed us to successfully manage a life-threatening case of acute anaerobic septic shock triggered by descending necrotizing mediastinitis. Case presentation: We admitted a 38-year-old critically ill Kosovar Albanian man to our intensive care unit because of clinical manifestations of severe sepsis. His condition had worsened in the previous 2 weeks following unsuccessful antibiotic therapy for tonsillitis complicated by retropharyngeal abscesses. Computed tomography and intraoperative observations identified abscesses in the anterior and middle mediastinum regions and the distal part of the neck, directly on the border with the left lobe of the thyroid gland. Cultures indicated infections with α-hemolytic Streptococcus and Clostridium species: High procalcitonin and lactate levels, blood gas analysis, poor peripheral capillary oxygen saturation, and severe hemodynamic instability pointed to a case of acute septic shock. The entire treatment consisted of an aggressive antibiotic regimen, transthoracic and mediastinal surgical evacuation of the abscess, vacuum sealing drainage with a pleural chest tube, continuous venovenous hemodiafiltration using cytokine-adsorbing hemofilters, and extracorporeal blood hyperoxygenation. Conclusions: Efficient treatment of severe anaerobic sepsis resulting from descending necrotizing mediastinitis should build on a multidisciplinary approach. In support of first-line therapies with targeted antibiotics and surgical debridement, clinicians should consider alternative therapies such as continuous venovenous hemodiafiltration with cytokine-adsorbing hemofilters and hyperoxygenation.