Nebulizers are often interfaced to patients using facemasks, especially when the patient is sick and uncooperative. Tight-fitting masks are thought to improve drug delivery, but recent studies have indicated that facemask seal can impact facial and eye deposition of aerosol. The purpose of the present study was to define the factors that influence drug delivery to the lung in pediatric patients using nebulizers and facemasks; particularly the roles of facemask seal, mask vents and nebulizer flow. Using a pediatric face facsimile and radiolabeled saline aerosols front-loaded and bottom-loaded nebulizers were tested for aerosol delivery during a pediatric pattern of breathing. Gamma scintigraphy provided images of the face. Filters measured drug delivery to the patient (inhaled mass [IM]). All data were reported as percent (%) nebulizer charge. Nebulizer flows of 4 and 8 L/min were tested. Preliminary experiments suggested that inertial forces between the edge of the mask and the face were responsible for facial and eye deposition. Front-loaded nebulizers were more efficient than bottom-loaded systems in delivering drug to the patient but favored eye deposition. These observations led to the design of a mask prototype constructed to maximize aerosol delivery to the patient with reduced deposition on the face and in the eyes. Modifications included vents and specialized cutouts in the region of the eyes. A tight fitting front-loaded mask delivered an IM of 6.38 +/- 0.42% (mean +/- SE) with facial and eye deposition of 1.76 +/- 0.17% and 1.14 +/- 0.15% respectively. The presence of specialized eye cutouts minimized facial and eye deposition (0.72 +/- 0.07%, and 0.15 +/- 0.02% [P < 0.0001]), even in the presence of increased nebulizer flow. The prototype design at 4 L/min maximized IM to 8.78 +/- 0.98% and further reduced facial and eye deposition (0.66 +/- 0.07% and 0.09 +/- 0.01%). Commercial bottom loaded masks reduced IM to 2.33 +/- 0.22%, with significant deposition on the face (1.43 +/- 0.16%). For aerosol therapy with nebulizers in pediatric patients, facemask design is a key factor in maximizing aerosol delivery to the patient while minimizing deposition on the face and in the eyes.