We simulated the intra-acinar contribution to phase III slope (S(acin)) for gases of differing diffusivities (He and SF(6)) by solving equations of diffusive and convective gas transport in multi-branch-point models (MBPM) of the human acinus. We first conducted a sensitivity study of S(acin) to asymmetry and its variability in successive generations. S(acin) increases were greatest when asymmetry and variability of asymmetry were increased at the level of the respiratory bronchioles (generations 17-18) for He and at the level of the alveolar ducts (generations 20-21) for SF(6), corresponding to the location of their respective diffusion fronts. On the basis of this sensitivity study and in keeping with reported acinar morphometry, we built a MBPM that actually reproduced experimental S(acin) values obtained in normal subjects for He, N(2), and SF(6). Ten variants of such a MBPM were constructed to estimate intrinsic S(acin) variability owing to peripheral lung structure. The realistic simulation of S(acin) in the normal lung and the understanding of how asymmetry affects S(acin) for different diffusivity gases make S(acin) a powerful tool to detect structural alterations at different depths in the lung periphery.