Objective: To determine the therapeutic efficacy and safety of plasmapheresis in the treatment of patients with severe sepsis and septic shock. Design: Prospective, randomised, clinical trial with a planned, midstudy, interim analysis. Setting: Intensive care unit in a university hospital in Archangels, Russia. Patients: Consecutive patients with severe sepsis or septic shock. Interventions: One hundred and six patients were randomised to receive either standard therapy or an add-on treatment with plasmapheresis. Measurements and results:The primary endpoint was 28-day survival. Septic shock was diagnosed in 57% of the plasmapheresis-treated patients and 54% of the control patients. Mean APACHE III score at entry was 56.4 in the plasmapheresis group and 53.5 in the control group. The 28-day, all-cause mortality rate was 33.3% (18/54) in the plasmapheresis group and 53.8% (28/52) in the control group. This represents a relative risk for fatal outcome in the plasmapheresis group of 0.61, an absolute risk reduction of 20.5% and a number of patients needed to treat of 4.9. Apart from six transient episodes of hypotension and one allergic reaction to fresh frozen plasma, no adverse reactions were attributable to the plasmapheresis treatment in this study. Conclusions: Plasmapheresis may be an important adjuvant to conventional treatment to reduce mortality in patients with severe sepsis or septic shock. Plasmapheresis is a safe procedure in the treatment of septic patients. A prospective randomised multicentre trial is warranted to confirm our results and to determine which subgroups of septic patients will benefit most from this treatment modality.