In most patients, the deposition of aerosolized pentamidine (AP) is less in the apex of the lung relative to the base. As the apex of the lung is relatively less ventilated than the base, it is possible that reduced regional ventilation may explain the inhomogeneity in regional drug deposition. The purpose of this study was to measure the relationship between regional deposition of AP and regional ventilation, and the influence of particle size and airway caliber on this relationship. Ten subjects with HIV infection who were receiving prophylaxis with AP were recruited. Using krypton (81mKr), we measured regional ventilation during treatment with AP, labeled with 99mTc. Two nebulizers were used (Respirgard II and Fisoneb) that produced particles of different size. In addition, patients were studied with and without a bronchodilator because changes in airway geometry can affect sites of particle deposition. There was no significant correlation between regional ventilation and regional particle deposition (r = 0.00, linear regression). Particle deposition in the upper lobes relative to the lower lobes was less than would be predicted by regional ventilation, by a ratio of 0.84 +/- 0.03 (mean +/- SE). Using two-way analysis of variance (ANOVA), the upper to lower zone deposition pattern was not affected by either nebulizer or by the use of albuterol. The Fisoneb had significantly more central deposition relative to the jet nebulizer (mean +/- SE, skC/P: Fisoneb 1.3 +/- 0.1, Respirgard 1.1 +/- 0.1, p = 0.005, two-way ANOVA). The use of a bronchodilator did not significantly affect the central/peripheral deposition pattern. We conclude that differences in deposition between upper and lower lung regions are not accounted for simply by differences in regional ventilation in patients undergoing prophylaxis with AP. In assessing the cause of regional inhomogeneities of pharmaceutical aerosol deposition (and in devising strategies to achieve more uniform distribution), regional ventilation should be measured directly rather than be inferred from the deposition pattern of the aerosol.