Purpose: The paper aims at investigating the adoption of Lean Six Sigma (LSS) in healthcare, grasping the state of the art and the level of the knowledge in this topic. Methodology: A systematic literature review was performed following a detailed review protocol created to select and study the papers interesting for the theme. A descriptive analysis of the selected database was conducted, investigating the country of origin, the year of publication, the journal, the research method. The content analysis was performed to synthesize the objectives, the field of application, the adopted tools and techniques, the results, the limitations of the LSS projects and their potential future elements to be considered and improved. Moreover, the authors caught the obstacles, the team building, and the timing of the projects reported in the papers. Findings: Most of the 43 selected papers are published in journals indexed in Scopus and in PubMed. Half of them regard publication outlets indexed in Web of Science. Moreover, the papers come mostly from USA and from Europe and they were published mainly in "Quality Management in Health Care". The papers are classified into: 5 systematic literature reviews, 1 grey literature review, 4 conceptual papers, 1 opinion paper, a paper with model conceptualization and 32 empirical papers. The projects of LSS reported in the extracted literature were performed mostly in emergency medicine, but there are also projects regarding the improvement of support processes. A multidisciplinary team is usually defined and trained at the beginning of the project. At least one LSS expert employed inside or outside the healthcare organization trains the trainers of the future through an initial training session and coaching the team during the project. Different tools and techniques were adopted, mainly using the cycle of Define-Measure-Analyse-Improve-Control (DMAIC), in order to pursue and obtain different types of performances, concerning the healthcare efficiency and the improvement of clinical quality. Staff development (in terms of improved performance and staff empowerment), and enhanced communication between staff and patients or among healthcare staff come out as additional positive effects of LSS, not explicitly defined in the project objectives. Moreover, the results of the content analysis demonstrate that LSS projects are usually implemented within 6 months, but the assessments of patient and staff satisfaction are neglected in the literature and hence they deserve more attention in future projects. Implication/ value: Even if the application of LSS has to be customized to the specific healthcare context, the diffusion of LSS experiences is fundamental to trigger the realization of other projects in the same or in different healthcare settings. The research provides academics and practitioners with the key factors that define successful LSS projects, reducing wastes and variability of processes and improving quality in healthcare.