We report the clinical findings and the results of inhalation challenge with toluene diisocyanate (TDI) and methacholine in 113 subjects with a history of exposure to TDI and work-related respiratory symptoms. Only some of the subjects (40.7%) had isocyanate asthma, diagnosed by a positive TDI inhalation challenge. Most reactors had a dual (30.4%) or a late (41.3%) response. The interval between the last occupational exposure and the specific challenge was significantly shorter in reactors, and among this group the number of immediate reactions to TDI decreased progressively with an increasing interval. The reactors had a significantly higher proportion of positive responses to methacholine and a significantly lower mean PD15 FEV-1 (provocative dose of methacholine which provoke a 15% decrease in forced expiratory volume in 1 second) (reactors: 557 micrograms, SEM 92.3; nonreactors: 1346 micrograms, SEM 128, P less than .01). Methacholine challenge could not identify subjects with isocyanate asthma.