PURPOSE AND SETTING: This review aimed to evaluate the effectiveness of strategies to implement clinical guidelines for chronic disease management in primary care in EU Member States. METHODS: We conducted a systematic review of interventional studies assessing the implementation of clinical guidelines. We searched five databases (EMBASE, MEDLINE, CENTRAL, Eppi-Centre and Clinicaltrials.gov) following a strict Cochrane methodology. We included studies focusing on the management of chronic diseases in adults in primary care. RESULTS: A total of 21 studies were found. The implementation strategy was fully effective in only four (19%), partially effective in eight (38%), and not effective in nine (43%). The probability that an intervention would be effective was only slightly higher with multifaceted strategies, compared to single interventions. However, effect size varied across studies; therefore it was not possible to determine the most successful strategy. Only eight studies evaluated the impact on patients' health and only two of those showed significant improvement, while in five there was an improvement in the process of care which did not translate into an improvement in health outcomes. Only four studies reported any data on the cost of the implementation but none undertook a cost-effectiveness analysis. Only one study presented data on the barriers to the implementation of guidelines, noting a lack of awareness and agreement about clinical guidelines. CONCLUSION: Our results reveal that there are only a few rigorous studies which assess the effectiveness of a strategy to implement clinical guidelines in Europe. Moreover, the results are not consistent in showing which strategy is the most appropriate to facilitate their implementation. Therefore, further research is needed to develop more rigorous studies to evaluate health outcomes associated with the implementation of clinical guidelines; to assess the cost-effectiveness of implementing clinical guidelines; and to investigate the perspective of service users and health service staff.