Rationale, aims, and objectivesLean Six Sigma (LSS) has been recognized as an effective management tool for improving healthcare performance. Here, LSS was adopted to reduce the risk of healthcare‐associated infections (HAIs), a critical quality parameter in the healthcare sector.MethodsLean Six Sigma was applied to the areas of clinical medicine (including general medicine, pulmonology, oncology, nephrology, cardiology, neurology, gastroenterology, rheumatology, and diabetology), and data regarding HAIs were collected for 28,000 patients hospitalized between January 2011 and December 2016. Following the LSS define, measure, analyse, improve, and control cycle, the factors influencing the risk of HAI were identified by using typical LSS tools (statistical analyses, brainstorming sessions, and cause‐effect diagrams). Finally, corrective measures to prevent HAIs were implemented and monitored for 1 year after implementation.ResultsLean Six Sigma proved to be a useful tool for identifying variables affecting the risk of HAIs and implementing corrective actions to improve the performance of the care process. A reduction in the number of patients colonized by sentinel bacteria was achieved after the improvement phase.ConclusionsThe implementation of an LSS approach could significantly decrease the percentage of patients with HAIs.