Purpose: The purpose of this paper is to illustrate the systematic role played by Six Sigma methodology in improving the quality of healthcare. The literature review identifies the relevant opportunities for successful introduction and development of Six Sigma approach in healthcare sector. Design/methodology/approach: A systematic methodology to identifying literature on Six Sigma in healthcare is presented. Web of Science, Medline, Emerald Insight, ASQ and ProQuest databases (1998-2016) were searched, and 68 papers of fair methodological quality were identified. Findings: The findings of the systematic review reveal a growing interest in research on Six Sigma adoption in healthcare. The findings indicate that Six Sigma applications in healthcare have been focused on the entire hospital with no real focus on a particular department or function. The key findings on benefits, success factors, challenges and common tools of Six Sigma from the existing literature are also presented in the paper. Research limitations/implications: The papers included in the systematic review were peer-reviewed papers available in English. Due to these limitations, relevant papers may have been excluded. Moreover, the authors have excluded all conference and white papers for their inclusion in this study. Originality/value: This paper can serve as a guide on how Six Sigma approach can be applied to improve the quality of healthcare. The authors also believe that this is possibly the most comprehensive systematic literature review on the topic and will set the foundation for various research avenues based on the key findings of this study. © 2018, Emerald Publishing Limited.