OBJECTIVE Although crackles are frequently heard on auscultation of the chest of patients with common cardiopulmonary disorders, the mechanism of production of these sounds is inadequately understood. The goal of this research was to gain insights into the mechanism of crackle generation by systematic examination of the relationship between inspiratory and expiratory crackle characteristics. METHODS Patients with a significant number of both inspiratory and expiratory crackles were examined using a multichannel lung sound analyzer. These patients included 37 with pneumonia, 5 with heart failure, and 13 with interstitial fibrosis. Multiple crackle characteristics were calculated for each crackle, including frequency, amplitude, crackle transmission coefficient, and crackle polarity. RESULTS Spectral, temporal, and spatial characteristics of expiratory and inspiratory crackles in these patients were found to be similar, but two characteristics were strikingly different: crackle numbers and crackle polarities. Inspiratory crackles were almost twice as numerous as expiratory crackles (n = 3,308 vs 1,841) and had predominately negative polarity (76% of inspiratory crackles vs 31% of expiratory crackles). CONCLUSIONS These observations are quantitatively consistent with the so-called stress-relaxation quadrupole hypothesis of crackle generation. This hypothesis holds that expiratory crackles are caused by sudden airway closure events that are similar in mechanism but opposite in sign and far less energetic than the explosive opening events that generate inspiratory crackles. We conclude that the most likely mechanism of crackle generation is sudden airway closing during expiration and sudden airway reopening during inspiration.