The aim of this study was to compare the Multistage Liquid Impinger (MSLI) and the Andersen Cascade Impactor (ACI) with respect to their power to predict differences in side effects of salbutamol delivered by a dry powder inhaler. Three preparations with the same nominal dose and the same inhaler device but generating aerosols with different aerodynamic particle size distributions were administered to six healthy volunteers in a randomized, placebo-controlled, four-way crossover study. Cumulative doses from 400 up to 1600 microg were given. The serum potassium level (K+-serum) and the heart rate (HR) were measured at baseline and 15 min after each dose. Both the MSLI and ACI showed large differences between the aerodynamic particle size distributions of the three preparations. The decrease in K+-serum revealed significant differences between the three active preparations and was significant for doses of 800 microg and higher. The HR results showed differences between the active preparations only at a nominal dose of 1600 microg and only for the preparation with the highest fine particle dose (FPD) compared to the other two preparations. The K+-serum appears to be a more sensitive measure for side effects than the HR. In vivo-in vitro correlations (IVIVCs) were established between the amounts of salbutamol deposited on the various cumulative impactor stages and the K+-serum. The best IVIVCs were obtained in the FPD range, resulting in correlation coefficients of at least 0.78. It is concluded that cascade impactor results in the FPD range of the MSLI as well as the ACI correlate well with the K+-serum. Cascade impactor analysis thus provides a clinically meaningful tool in the development and the quality control of salbutamol inhalation powders.