Fluticasone propionate pressurized metered dose inhalers (pMDIs) containing the hydrofluoroalkane (HFA) propellant, HFA 134a, are being developed to replace existing chlorofluorocarbon (CFC) pMDIs. This is part of the ongoing worldwide project to limit the damage to the earth's ozone layer. The in vivo performance and dose proportionality of fluticasone propionate HFA 134a pMDIs was examined for fluticasone propionate doses of 400, 1000 and 2000 microg using the 50, 125 and 250 microg strength pMDIs, respectively. The 125 and 250 microg strength HFA 134a pMDIs were compared with corresponding fluticasone propionate CFC pMDIs. Twenty-three healthy subjects participated in this single dose, randomized, five-way, cross-over study. Serial blood samples were collected 24 h post-dose to measure fluticasone propionate plasma concentrations. Twenty-four hour urinary-free cortisol was also measured before and after dosing. A dose-proportional increase in plasma fluticasone propionate concentrations was observed with increasing dose for the HFA 134a pMDIs. This was associated with a dose-related decrease in urinary cortisol excretion. Similar or lower fluticasone propionate systemic exposure was observed with the HFA 134a pMDIs compared to the corresponding CFC inhalers. The differences in systemic exposure observed for the HFA 134a and CFC pMDIs were too small to produce a differential effect on urinary cortisol excretion. Since fluticasone propionate has negligible oral bioavailability, the systemic exposure, which arises only from pulmonary absorption, is a measure of lung deposition. There was a good correlation between the in vitro fine particle mass produced by the different strengths and types of pMDI and the systemic exposure to fluticasone propionate. Therefore, the fluticasone propionate HFA 134a pMDI is an acceptable pharmaceutical alternative to the current CFC pMDI, producing similar lung deposition and no increase in systemic exposure at microgram equivalent doses.