Post-traumatic stress disorder (PTSD) is a common mental health condition that requires exposure to a traumatic event. This provides unique opportunities for prevention that are not available for other disorders. The aim of this review was to undertake a systematic review and evaluation of randomized controlled trials (RCTs) of interventions designed to prevent PTSD in adults. Searches involving Cochrane, Embase, Medline, PsycINFO, PILOTS and Pubmed databases were undertaken to identify RCTs of pre-incident preparedness and post-incident interventions until May 2019. Six pre-incident and 69 post-incident trials were identified that could be included in meta-analyses. The overall quality of the evidence was low. There was emerging evidence that some interventions may be helpful but an absence of evidence for any intervention that can be strongly recommended for universal, selected or indicated prevention before or within the first three months of a traumatic event. The strongest results were found for cognitive-behavioural therapy with a trauma focus (CBT-T) in individuals with a diagnosis of acute stress disorder which supports calls to detect and treat individuals with significant symptoms rather than providing blanket preventative interventions. Further research is required to optimally configure existing interventions with some evidence of effect and to develop novel interventions to address this major public health issue.