Although small area effects on health-related quality of life (HRQoL) have been extensively studied, less is known at the regional level, particularly in France where no multilevel evidence is available. Using data from a large representative cross-sectional survey conducted in 2003 (N=16 732), this study explores individual and regional determinants of the SF-36 Physical Functioning and Mental Health subscales. We considered a causal pathway leading from deindustrialization to HRQoL and assessed the roles of net migratory flows, deprivation, and the social and physical environments. Worse HRQoL results were found in regions most affected by deindustrialization, with evidence for mediating effects of migration, voter abstention rate and individual health-related behaviors. Cross-level interactions and intraregional heterogeneity were also found, confirming the complexity of individual-area relationships and the need for carefully conceptualized multilevel analyses to guide health policies effectively.