Purpose: This study aims to examine the effect of human resource management (HRM) in mitigating negative effects of Lean management and Six Sigma (LM&SS) on employee well-being in health care. The authors subdivide well-being into three components: happiness, trust and health. Design/methodology/approach: This is a cross-sectional, multisite survey study in internal service units of hospitals. Data analyzed using multivariate regression come from a sample of 1,886 survey respondents (42 units, N = 218 supervisors, N = 1,668 employees) in eight Dutch academic hospitals that have implemented LM&SS. Findings: The present study findings show no or weak effects of LM&SS on the happiness and health component of employee well-being. In addition, the authors found a significant but weak direct positive effect (ß = 0.07) of the LM&SS bundle on the trusting relationships component of well-being. Therefore, moderating effects of HRM practices on the relationship between LM&SS and employee well-being seem less relevant because an existing relationship between LM&SS and employee well-being is a prerequisite for moderation (Hayes, 2009). There were unexpected side effects. Inspired by research that discusses direct effects of HRM on employee well-being, the authors tested this relationship and found that HRM has a direct positive effect on trust and happiness of employees in health care. For the health component of well-being, the present results show a weak negative effect of HRM. Practical implications: This study results in a cautiously optimistic view about LM&SS in health care, provided that it is applied in a targeted manner (to improve the performance of their processes) and that HRM is strategically aligned with the goals of LM&SS to improve employees’ happiness and trusting relationships. Originality/value: Unique features of the study are the focus on the consequences for employees’ well-being related to LM&SS in health care, the role of HRM in regard to this relationship and the participation of all eight Dutch academic hospitals in this research.