Objectives: Although blood purification improves outcomes in animal studies of sepsis, results of clinical trials have been mixed. We conducted a systematic review and meta-analysis of randomized trials to determine the association between various blood purification techniques and all-cause mortality in humans with sepsis. Data Sources: We searched for relevant studies in MEDLINE, EMBASE, and the Cochrane Library database from January 1966 to May 2012. Study Selection: Inclusion required a diagnosis of sepsis and comparison of blood purification techniques including hemofiltration, hemoperfusion, plasma exchange, or hemodialysis with no blood purification (control group). Data Extraction: Two authors independently selected studies and extracted data. Summary statistics, risk ratios, and CIs were calculated using random-effects modeling. Study quality was assessed using Jadad score, and publication bias was assessed using funnel plots and Egger's statistic. Data Synthesis: Overall, blood purification decreased mortality compared with no blood purification (35.7% vs 50.1%; risk ratio, 0.69 [95% CI, 0.56-0.84]; p < 0.001; 16 trials, n = 827). However, these results were driven mainly by hemoperfusion (risk ratio, 0.63 [95% CI, 0.50-0.80]; p < 0.001; 10 trials, n = 557) and plasma exchange (risk ratio, 0.63 [95% CI, 0.42-0.96]; p = 0.03; two trials, n = 128). Pooling of all trials of blood purification for treatment of sepsis was no longer associated with lower mortality (risk ratio, 0.89 [95% CI, 0.71-1.13]; p = 0.36; eight trials, n = 457) after excluding trials using polymyxin B hemoperfusion. Conclusions: Blood purification techniques including hemoperfusion, plasma exchange, and hemofiltration with hemoperfusion were associated with lower mortality in patients with sepsis. These results were mainly influenced by studies using polymyxin B hemoperfusion from Japan.