Airflow obstruction and heterogeneities in airway constriction and ventilation distribution are well-described prominent features of asthma. However, the mechanistic link between these global and regional features has not been well defined. We speculate that peripheral airway resistance (R p) may provide such a link. Structural and functional parameters are estimated from PET and HRCT images of asthmatic (AS) and nonasthmatic (NA) subjects measured at baseline (BASE) and post-methacholine challenge (POST). Conductances of 35 anatomically defined proximal airways are estimated from airway geometry obtained from high-resolution computed tomography (HRCT) images. Compliances of sublobar regions subtended by 19 most distal airways are estimated from changes in regional gas volume between two lung volumes. Specific ventilations (sV) of these sublobar regions are evaluated from 13NN-washout PET scans. For each pathway connecting the trachea to sublobar region, values of Rp required to explain the sV distribution and global airflow obstruction are computed. Results show that Rp is highly heterogeneous within each subject, but has average values consistent with global values in the literature. The contribution of Rp to total pathway resistance (RT) increased substantially for POST (P < 0.0001). The fraction Rp/RT was higher in AS than NA at POST (P < 0.0001) but similar at BASE (range: 0.960-0.997, median: 0.990). For POST, Rp/RT range was 0.979-0.999 (NA) and 0.981-0.995 (AS). This approach allows for estimations of peripheral airway resistance within anatomically defined sublobar regions in vivo human lungs and may be used to evaluate peripheral effects of therapy in a subject specific manner. Copyright © 2013 the American Physiological Society.