Wheeze is a classic sign of airflow obstruction but relatively little is known of its mechanism of production or its relationship to the development of airflow obstruction. We studied eight asthmatic subjects age (mean +/- 5D) 42 +/- 5 yr, FEV1 2.46 +/- 0.36 L during an extended, symptom-limited methacholine challenge test. Breath sounds were detected by a microphone over the right upper anterior chest. Spectral analysis was by a fast Fourier transform algorithm. Mean FEV1 fell by 51 +/- 14% to 1.28 +/- 0.61 L during the challenge and airways resistance increased by 119 +/- 50%. There were no consistent changes in breathing pattern or tidal volume during the challenge. Wheeze occurred late in the challenge at the highest concentration of methacholine administered and only after expiratory tidal flow limitation had been reached. Five subjects developed wheeze on tidal breathing, the remaining three only wheezed on deep breathing. Wheezing sounds were reproducible between breaths, coefficient of variation of starting sound frequency was 4.2% and ending frequency 12%. Mean frequency of expiratory wheezes was 669 +/- 100 Hz and inspiratory wheezes 710 +/- 76 Hz. Expiratory wheeze fell in pitch during a breath (mean fall in sound frequency 187 +/- 43 Hz) but inspiratory wheezes were more variable. Expiratory wheezes occurred late in the respiratory cycle at a mean of 58% of the maximal tidal expiratory flow, whereas inspiratory wheezes occurred around maximal tidal inspiratory flows, suggesting that the mechanisms of production of inspiratory and expiratory wheezes may be different. In this model, the presence of wheeze during tidal breathing was a sign of severe airflow limitation.