The Andersen cascade impactor (ACI) and laser diffraction (LD) can be correlated at ambient temperature for aqueous drug formulations atomized by Soft Mist inhalers. A comparison of the two particle size determination methods at different conditions (flow rate, relative humidity) was performed. Under well-defined conditions, the faster LD can substitute the time consuming ACI at least for routine tests. The measurements were performed with three different drug formulations. The aerosol was generated by Soft Mist inhalers, and the droplet distributions were measured simultaneously using a laser diffraction analyzer together with the eight-stage Andersen cascade impactor. The simultaneous measurements ensure that aerosol and air conditions are identical for both LD and ACI. In order to measure the scattered laser light intensity of the aerosol passing the induction port, glass windows were fitted to the induction port. The evaporation effect of the aqueous aerosols on the PSD was investigated at ambient humidity and high humidity (RH > 90%). The simultaneous determination of the droplet size distribution leads to a good correlation between the ACI and LD method only if the measurements were performed at RH of >90%. The humidity of the ambient air had the strongest influence on PSD not only for ACI, but also for LD. In our set-up, the almost saturated air prevents aqueous droplets from drying. The influence of the flow rate on LD was negligible, whereas for ACI, a flow rate dependence is expected. The advantages of LD and the demonstrated compatibility to established EP/USP methods motivate the substitution of the ACI and the use of LD for routine measurements.