The safety, tolerability and pharmacokinetics of the chlorine-free propellant HFA134a were assessed in healthy subjects after single and repeat doses. Absorption and disposition were investigated in healthy subjects and severe chronic obstructive pulmonary disease (COPD) patients using labelled HFA134a. There were no clinically significant changes in vital signs, ECG, pulmonary function tests and laboratory parameters measured. No serious adverse events were reported. In both subjects and patients HFA134a was mainly eliminated by exhalation within the first few minutes after administration and was distributed throughout the body with no obvious accumulation in any specific region. HFA134a was rapidly absorbed after inhalation with dose-related blood concentrations which declined rapidly after dosing (t1/2 = 31 min). Metabolism was not a significant route of elimination of HFA134a. Studies were also performed with salmeterol and salbutamol MDIs reformulated with HFA134a. The results showed that these MDIs were safe and well tolerated in healthy subjects and gave a similar pharmacodynamic response to the current MDIs.