BACKGROUND: In an effort to identify factors producing a finest mist from Jet-Nebulizers we designed 2 mouthpieces with 4 different internal designs and 1-3 compartments.MATERIALS AND METHODS: Ten different drugs previous used with their "ideal" combination of jet-nebulizer, residual-cup and loading were used. For each drug the mass median aerodynamic diameter size had been established along with their "ideal" combination.RESULTS: For both mouthpiece, drug was the most important factor due the high F-values (Flarge=251.7, p<0.001 and Fsmall=60.1, p<0.001) produced. The design affected the droplet size but only for large mouthpiece (Flarge=5.99, p=0.001, Fsmall=1.72, p=0.178). Cross designs create the smallest droplets (2.271) so differing from the other designs whose mean droplets were greater and equal ranging between 2.39 and 2.447. The number of compartments in the two devices regarding the 10 drugs was found not statistically significant (p-values 0.768 and 0.532 respectively). Interaction effects between drugs and design were statistically significant for both devices (Flarge=8.87, p<0.001, Fsmall=5.33, p<0.001).CONCLUSION: Based on our experiment we conclude that further improvement of the drugs intended for aerosol production is needed. In addition, the mouthpiece design and size play an important role in further enhancing the fine mist production and therefore further experimentation is needed.