An acoustic whole body plethysmograph was developed to estimate specific airway resistance (sRaw) in unrestrained mice. The plethysmograph uses acoustic principles to measure the thoracic breathing pattern and simultaneously measures the airflow entering and/or leaving the plethysmograph. Similarly to traditional methods utilizing a double-chamber plethysmograph, these measurements were combined to estimate sRaw. To evaluate the new system, we placed six conscious A/J mice individually in a whole body plethysmograph (Buxco System) for a 2-min exposure to aerosolized methacholine chloride dissolved in saline (0, 5, 10, and 20 mg/ml), which is known to increase sRaw in mice. Three minutes after exposure, the mice were transferred to the acoustic plethysmograph for 2 min for data collection. The mean baseline value of sRaw was 0.93+/-0.10 cmH2O.s. A dose-dependent increase in sRaw was shown, with an approximate tripling of sRaw at the highest dose. These results demonstrate the ability of the system to estimate sRaw based on plethysmograph airflow and acoustic amplitude.