Objectives: To compare the systemic bioavailability (assessed by cortisol suppression) of high-dose budesonide when given by four inhaler devices and orally. Also studied are the relative systemic potencies of three inhaled steroids (budesonide, fluticasone propionate, and beclomethasone dipropionate) when given by metered-dose inhaler (MDI) with a large volume spacer., Design: Double-blind, crossover, placebo-controlled trial., Participants: Sixteen healthy, steroid-naive adult volunteers., Methods: On separate occasions, each subjects took 4 mg of budesonide through the following devices: MDI alone, MDI with 750-mL. spacer, dry-powder inhaler and nebulizer; 4 mg of budesonide was also taken orally to assess the effects of GI absorption. For the drug comparison, each subject took 4 mg of budesonide, fluticasone, and beclomethasone, and 2 mg of budesonide and fluticasone by MDI and spacer., Results: Greatest percent suppression (95% confidence interval) of 9:00 AM cortisol with budesonide was observed with MDI alone (73% [57 to 90]) and turbohaler (72% [58 to 86]) compared with MDI spacer (42% [22 to 64]) and oral administration (14% [+6- to -34]). Nebulized budesonide produced an insignificant rise in 9:00 AM cortisol level. The most suppressive drug (given by MDI spacer) was fluticasone at 4 mg (86% [82 to 91]) and at 2 mg (72% [59 to 85]). The least suppressive drug was budesonide at 4 mg (43% [22 to 64]) and at 2 mg (25% [3 to 47]). The effects of 4 mg of beclomethasone were intermediate (66% [49 to 82%])., Conclusions: The choice of delivery device for administration of budesonide can lead to important differences in systemic bioavailability. Fluticasone has greater systemic potency than budesonide or beclomethasone when given at microgram equivalent dosage. The systemic potency ratio of fluticasone propionate to budesonide in normal human volunteers in the present study is similar to the therapeutic potency ratio of the drug in asthmatic patients (approximately 2:1).