Thermal injury is extremely stressful and data characterising the systemic endocrine stress response to this injury are sparse. The objective of this study was to measure the effects of thermal injury on mice on corticosterone (Cort) levels in relation with corticosteroid-binding globulin (CBG) and thymus cell populations. The endocrine stress response was determining by measuring total-, free-Cort, CBG binding capacity (B_max), liver CBG mRNA and circulating CBG levels at 1, 2, 5 and 10 days post-burn. Thymus cell populations were also analyzed. Following thermal injury, a rapid increase of total Cort was observed in the first 48 hours. This was associated with a decrease of hepatic CBG mRNA , protein levels and CBG binding capacity. Percentage of free Cort in the burn group peaked at day 2 post-burn with a dramatic (+500%) increase. This correlated with a significant decrease of thymus cellularity (50% less). Phenotypic analyses showed that cortico-sensitive cells were significantly altered. Five days after treatment both endocrine and immune parameters returned to control levels. Our results demonstrate that following a thermal injury CBG is mainly responsible for Cort's action on cortico-sensitive immune cells.