INTRODUCTION: Following trauma, patients may suffer an overwhelming pro-inflammatory response and immune paralysis resulting in infection and multiple organ failure (MOF). Various potentially immunomodulative interventions have been tested. The objective of this study is to systematically review the randomized controlled trials (RCTs) that investigate the effect of potentially immunomodulative interventions in comparison to a placebo or standard therapy on infection, MOF, and mortality in trauma patients. METHODS: A computerized search of MEDLINE, the Cochrane CENTRAL Register of Controlled Trials, and EMBASE yielded 502 studies, of which 18 unique RCTs were deemed relevant for this study. The methodological quality of these RCTs was assessed using a critical appraisal checklist for therapy articles from the Centre for Evidence Based Medicine. The effects of the test interventions on infection, MOF, and mortality rates and inflammatory parameters relative to the controls were recorded. RESULTS: In most studies, the inflammatory parameters differed significantly between the test and control groups. However, significant changes in infection, MOF, and mortality rates were only measured in studies testing immunoglobulin, IFN-γ, and glucan. CONCLUSIONS: Based on level 1b and 2b studies, administration of immunoglobulin, IFN-γ, or glucan have shown the most promising results to improve the outcome of trauma patients.