Background: While health care services are beginning to implement system-wide patient safety interventions, evidence on the efficacy of these interventions is sparse. We know that uptake can be variable, but we do not know the factors that affect uptake or how the interventions establish change and, in particular, whether they influence patient outcomes. We conducted a systematic review to identify how organisational and cultural factors mediate or are mediated by hospital-wide interventions, and to assess the effects of those factors on patient outcomes. Methods: A systematic review was conducted and reported in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Database searches were conducted using MEDLINE from 1946, CINAHL from 1991, EMBASE from 1947, Web of Science from 1934, PsycINFO from 1967, and Global Health from 1910 to September 2012. The Lancet, JAMA, BMJ, BMJ Quality and Safety, The New England Journal of Medicine and Implementation Science were also hand searched for relevant studies published over the last 5 years. Eligible studies were required to focus on organisational determinants of hospital- and system-wide interventions, and to provide patient outcome data before and after implementation of the intervention. Empirical, peer-reviewed studies reporting randomised and non-randomised controlled trials, observational, and controlled before and after studies were included in the review. Results: Six studies met the inclusion criteria. Improved outcomes were observed for studies where outcomes were measured at least two years after the intervention. Associations between organisational factors, intervention success and patient outcomes were undetermined: organisational culture and patient outcomes were rarely measured together, and measures for culture and outcome were not standardised. Conclusions: Common findings show the difficulty of introducing large-scale interventions, and that effective leadership and clinical champions, adequate financial and educational resources, and dedicated promotional activities appear to be common factors in successful system-wide change. The protocol has been registered in the international prospective register of systematic reviews, PROSPERO (Registration No. CRD42103003050).