1. The aim of the present study was to assess the role of the nitric oxide (NO) system in cortisol-induced hypertension in humans. 2. Plasma and urinary nitrate/nitrite concentrations and plasma concentrations of arginine and symmetric (SDMA) and asymmetric (ADMA) dimethyl arginine were measured in six subjects on a restricted nitrate diet who were treated with 80 mg/day cortisol and in subjects on an unrestricted nitrate diet who were treated with cortisol (80 mg/day, n = 6, or 200 mg/day, n = 10) for 5 days. 3. Cortisol significantly increased systolic and mean arterial pressure. Significant reductions in plasma nitrate/nitrite concentrations were observed in subjects on a restricted nitrate diet on days 3, 4 and 5 of cortisol treatment (to 11 +/- 1, 10 +/- 1, 11 +/- 1 pmol/L, respectively) compared with pretreatment (16 +/- 1 pmol/L; P < 0.01). There were no significant changes in plasma arginine, ADMA or SDMA concentrations. 4. Cortisol treatment significantly increased blood pressure and reduced plasma nitrate/nitrite concentrations. Reductions in plasma nitrate concentrations are not explained by changes in substrate availability or in endogenous nitric oxide synthase inhibitors. These data support a role for the NO system in cortisol-induced hypertension in humans.