Background: Polymyxin B hemoperfusion is a strategy to remove circulating endotoxin in patients with sepsis. Previous systematic reviews derived from randomized and non-randomized studies suggested that use of polymyxin B hemoperfusion reduced mortality, based on the pooled data from various time points in the clinical course of sepsis. We conducted a meta-analysis of randomized controlled trials to assess the impact of polymyxin B hemoperfusion specifically on 28-day mortality in patients with sepsis and septic shock. Methods: PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials were searched for eligible trials from inception through July 30, 2017. All randomized controlled trials were eligible if they examined the impact of polymyxin B hemoperfusion on 28-day mortality in patients with sepsis and septic shock. Risk of bias was evaluated with the Cochrane risk of bias assessment tool. Data were pooled using the DerSimonian and Laird random-effects model. Results: Seven trials involving 586 participants were identified for the analysis. Use of polymyxin B hemoperfusion was not associated with a reduced risk of 28-day mortality [risk ratio (RR), 0.76; 95% CI, 0.54–1.07] compared with usual care. One unpublished trial also showed no significant 28-day survival benefit. Conclusions: There is no evidence to support the use of polymyxin B hemoperfusion for patients with sepsis and septic shock with respect to 28-day mortality.