To determine the predictive value of wheeze compared to methacholine inhalation challenge (MIC) in diagnosing asthma, we prospectively evaluated 34 patients considered to be difficult diagnostic problems, referred with a history of wheeze. On the basis of MIC results, 12 patients had hyperreactive airways consistent with asthma, while 22 had airways that were no more reactive than those of normal controls. Compared to MIC, a history of wheeze was predictive of hyperreactive airways 35 percent of the time, a prior clinical diagnosis of asthma 62 percent, and scattered monophonic expiratory wheeze 43 percent. We conclude that: (1) a history of wheeze, a prior clinical diagnosis of asthma, and expiratory wheezing on physical examination are much less reliable than MIC in predicting the presence or absence of asthma; (2) these parameters cannot be used as reliable epidemiologic markers for asthma; and (3) the clinical suspicion of asthma should be confirmed by bronchoprovocation challenge or the demonstration by spirometry of reversible expiratory airflow obstruction.