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/leaving the plethysmograph. Similar to traditional methods utilizing a double chamber plethysmograph, these measurements were combined to estimate sRaw. To evaluate the new system, six conscious A/J mice were individually placed in a whole-body plethysmograph (Buxco System, Inc.) for a two minute 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 following exposure, the mice were transferred to the acoustic plethysmograph for two minutes for data collection. The mean baseline value of sRaw was 0.93 ± 0.10 cm H₂O sec. A dose-dependent increase in sRaw was demonstrated, 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.