Since the 1990s, most European countries have implemented activation policies targeting the unemployed. During the past decade, the target group for activation policies expanded and currently also includes persons with limitations in their ability to work due to long-term or chronic illness and disabilities. The argument underlying these policies is that labour-market exclusion is the main cause for social marginalization because participation in paid work provides important social and psychological functions that cannot be found elsewhere. Based on an extensive set of quantitative data that combines register data and survey data, and using structural equation modelling, this paper analyses the relationship between chronic illness and social marginalization, and in particular which role labour-market exclusion plays in this relationship. Is labour-market exclusion a crucial factor in explaining why individuals with chronic illnesses face a higher risk of social marginalization if factors such as income and education are also taken into account? From the statistical results, the paper states that individuals with chronic illnesses face a far higher risk of social marginalization, but that this risk is caused by their health limitations and not by their lack of labour-market participation. Contrary to the policies’ logic and the theoretical argument of psycho-social theories originating from the deprivation perspective, no direct, indirect or mediating effects of labour-market exclusion on social marginalization were identified.