Background: The increased burden of cancer has driven the development of health system level initiatives worldwide promoting early diagnosis. Although it is challenging to synthesize results of such complex, diverse initiatives, it is crucial to review the evidence to inform future programs and enhance transparency and accountability. Aim: We aimed to systematically review the literature on health system level initiatives promoting early diagnosis among the adult population, describing and categorizing their components, stakeholders, target populations, and outcomes. Methods: We have searched databases (including Embase, PsycInfo, Medline and ASSIA), Web sites (including charities, governmental and nongovernmental agencies) and reference lists of included studies and relevant systematic reviews for peer-reviewed publications and gray literature. We included quantitative, qualitative, mixed-methods studies and reviews/overviews about a single initiative in high-income countries as defined by the World Bank. We included initiatives: 1) targeting adults aged 18 or older; 2) aiming to promote early diagnosis; 3) addressing the patient/public and at least two more levels of contextual influence (according to a model of multilevel influences on cancer care); 4) implemented at a national level or equivalent. Study selection, quality assessment and data extraction were carried out independently by two reviewers. Narrative synthesis was used to analyze the findings. The review protocol has been published by BMJ Open and registered at PROSPERO (CRD42016047233). Results: Twenty initiatives from 10 countries were identified in 263 publications. Data were extracted from 104 core publications about 19 initiatives. It was possible to assess the quality of 35 core publications. Initiatives focused on fast-track for patients with alarm symptoms or other referral pathways for those with other symptoms or abnormal test results (n=11), national awareness campaigns for the public (n=4), and strategies with multiple components (n=4). Tools developed for professionals included referral guidelines and online referral systems. Initiatives focusing on referral pathways showed some improvements in diagnostic intervals, and limited evidence on the impact on staging. Performance targets were often not met. Results from awareness campaigns indicated improvement in awareness, but evidence about changes in health-seeking behavior was limited. Barriers and facilitators were described, including availability of specialist staff. Conclusion: Robustness of methods/outcomes could not always be assessed as several publications were reports or government documents. Evidence on the impact of initiatives regarding longer-term outcomes is limited. Described barriers and facilitators may help to inform future initiatives. Findings may be useful to researchers, policy makers, and governments developing early diagnosis programs and assessing cancer outcomes.