We explored the possibility of using a saline aerosol for bolus dispersion measurements to detect peripheral airway alterations in smokers. Indexes of ventilation inhomogeneity in conductive (S_cond) and acinar (S_acin) lung zones, as derived from the multiple-breath N₂ washout (Verbanck S, Schuermans D, Van Muylem A, Noppen M, Paiva M, and Vincken W, J Appl Physiol 83: 1807-1816, 1997), were also measured. The saline bolus test consisted of inhaling 60-ml saline aerosol boluses to different volumetric lung depths (VLD) in the 1.1 liter volume above functional residual capacity. In the never-smoker group (n = 12), saline boluses showed bolus dispersion values consistent with normal values reported in the literature for 0.5- to 1-µm aerosols. In the smoker group (n = 12; 28 ± 9 pack years, mean ± SD), significant increases were seen on dispersion and skew of the most peripherally inhaled saline boluses (VLD = 800 ml; P < 0.05) as well as on S_acin (P = 0.007) with respect to never-smokers. Shallow inhaled boluses (VLD = 200 ml) and S_cond did not reveal any significant differences between smokers and never-smokers. This study shows the consistent response of two conceptually independent tests, in which both saline aerosol and gas-derived indexes point to a heterogeneous distribution of smoking-induced structural alterations in the lung periphery.