Previous studies of patients with septic shock have independently demonstrated alterations in plasma concentrations of B-type natriuretic peptide and plasma free cortisol. Previous data suggest that a reciprocal relationship might exist. However, the relationship between these hormones in patients with septic shock is unclear. We sought to compare paired measurement of both B-type natriuretic peptide and plasma free cortisol in a study of septic shock patients. Twenty-one consecutive adult patients from a tertiary level, multidisciplinary intensive care unit underwent blood collection within 72 hours of developing septic shock. Mean ± SD Acute Physiology and Chronic Health Evaluation III score was 80.1 ± 23.8. Hospital mortality was 29%. Log plasma free cortisol demonstrated positive correlation with log B-type natriuretic peptide (r=0.55, P=0.019). Log plasma free cortisol also correlated with Acute Physiology and Chronic Health Evaluation III score (r=0.67, P <0.001) and noradrenaline dose (r=0.55, P=0.01). Acute Physiology and Chronic Health Evaluation III (P=0.001) and noradrenaline dose (P=0.02) were independent predictors of plasma free cortisol. A model incorporating both variables explained 68% of variation in plasma free cortisol (R-square=0.682). This study of patients with septic shock demonstrates a previously unappreciated positive correlation between plasma free cortisol and b-type natriuretic peptide concentration. Acute Physiology and Chronic Health Evaluation III score and noradrenaline dose were independent predictors of plasma free cortisol.