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BACKGROUND Massive bleeding is a major cause of death both in trauma and nontrauma patients. In trauma patients, the implementation of massive transfusion protocols (MTP) led to improved outcomes. However, the majority of patients with massive bleeding are nontrauma patients. OBJECTIVES To assess if the implementation of MTP in nontrauma patients with massive bleeding leads to improved survival. DATA SOURCES National Library of Medicine's Medline database (PubMed). STUDY ELIGIBILITY CRITERIA Original research articles in English language investigating MTP in nontrauma patients. PARTICIPANTS Nontrauma patients with massive bleeding 18 years or older. INTERVENTION Transfusion according to MTP versus off-protocol. STUDY APPRAISAL AND SYNTHESIS METHODS Systematic literature review using PubMed. Outcomes assessed were mortality and transfused blood products. Studies that compared mortality of MTP and non-MTP groups were included in meta-analysis using Mantel-Haenszel random effect models. RESULTS A total of 252 abstracts were screened. Of these, 12 studies published 2007 to 2017 were found to be relevant to the topic, including 2,475 patients. All studies were retrospective and comprised different patient populations. Most frequent indications for massive transfusion were perioperative, obstetrical and gastrointestinal bleeding, as well as vascular emergencies. Four of the five studies that compared the number of transfused blood products in MTP and non-MTP groups revealed no significant difference. Meta-analysis revealed no significant effect of MTP on the 24-hour mortality (odds ratio 0.42; 95% confidence interval 0.01–16.62; p = 0.65) and a trend toward lower 1-month mortality (odds ratio 0.56; 95% confidence interval 0.30–1.07; p = 0.08). LIMITATIONS Heterogeneous patient populations and MTP in the studies included. CONCLUSION There is limited evidence that the implementation of MTP may be associated with decreased mortality in nontrauma patients. However, patient characteristics, as well as the indication and definition of MTP were highly heterogeneous in the available studies. Further prospective investigation into this topic is warranted. LEVEL OF EVIDENCE Systematic review and meta-analysis, level III.