Studies using dry powder devices have suggested that fluticasone propionate (FP) has a greater systemic effect than budesonide (BUD). The aim of the present study was to investigate and compare the relative systemic potency of FP and BUD from their respective pressurized metered-dose inhalers (pMDIs). A placebo-controlled, open, randomized, cross-over study was conducted in 21 healthy male volunteers. Placebo, BUD (200, 400 and 1,000 micrograms b.i.d.) and FP (200, 375 and 1,000 micrograms b.i.d.) were inhaled for 4 days, with a wash-out period of at least 3 days between treatments. Blood samples for cortisol analysis were drawn during the last 24 h of each treatment period. Cortisol levels, measured as 24 h pooled plasma cortisol, were statistically significantly lower (p = 0.0001) for all dose levels during FP pMDI treatment (21, 39 and 84% suppression from placebo) than during BUD pMDI treatment (1, 3 and 27% suppression from placebo). The relative systemic potency FP:BUD was 3.7:1 (95% confidence interval (95% CI) 2.9-4.8)). The relative systemic potency based on the single 08:00 h samples was 5.2:1 (95% CI 3.0-9.3). In conclusion, in healthy male volunteers using pressurized metered-dose inhalers, fluticasone propionate was shown to have a stronger systemic effect than budesonide.