Regarding the effects of High-Performance Work Systems (HPWS), we can draw two conclusions. First, existing studies on the effects of HPWS on employees' well-being at work are scarce. Second, few studies have considered the relationships between HPWS and work-to-family interface (i.e., work-to-family enrichment, WFE; and work-to-family conflict, WFC). Only one previous study conducted on a Portuguese sample (i.e., Carvalho & Chambel, 2016) has examined the relationships between these concepts in a comprehensive model. Our study aims to replicate one part of Carvalho and Chambel's model but also to extend previous work. We investigated a model of HPWS-employees' well-being at work (i.e., job engagement and job strain) relationships by considering work-to-family interface as a mediator. We surveyed 170 employees of a Belgian company. Data were analysed using structural equation modelling and bootstrapping method. WFE partially mediates the relationships between HPWS and job engagement, whereas WFC partially mediates the relationships between HPWS and job strain. Our study, confirming the results of Carvalho and Chambel (2016), highlights the important role of HPWS in the development of employees' well-being at work. Working in an organization where HPWS are applied leads employees to perceive more enrichment and less conflict between their work and family lives, making them more engaged in and less stressed by their work.