Increasing concentrations of inhaled aerosolized histamine acid phosphate were administered to 31 heavy cigarette smokers from a smoking cessation clinic. Nineteen of 31 smokers (mean age +/- ISD: 39.6 +/- 11.5 yrs; pack years 25.5 +/- 13.5) failed to reduce forced expired volume in one second (FEV1) while inhaling histamine and were labelled nonresponders. In 12 of 31 smokers (age 38.4 +/- 9.4 yrs; pack years 23.0 +/- 10.5), extrapolated provocation concentration of inhaled histamine required to reduce forced expired volume in one second (FEV1) by 10 percent (PC10) could be determined and these smokers were labelled responders. We also measured maximum expiratory flow volume curves with air and also a mixture of 80 percent helium and 20 percent oxygen (HeO2) to determine the percentage of increase in maximal flow at 50 percent vital capacity breathing HeO2 as compared to air (delta Vmax50), and the slope of phase III of the single breath oxygen test (delta N2/L). In the responders, PC10 ranged from 1.4 mg/ml to 10.2 mg/ml (mean 5.5 +/- 3.3 mg/ml) and delta Vmax50 ranged from 7.1 percent to 68.4 percent (mean 39.6 +/- 18.3 percent). There was a significant positive correlation between PC10 and delta Vmax50 (r = 0.77, p less than 0.01), and a significant negative correlation between PC20 and delta N2/L (r = -.61, p less than 0.01). There was no difference between responders and nonresponders in mean values for lung function tests, allergy skin tests, or symptoms. These results suggest that there may be two fundamentally different groups of smokers with peripheral airways dysfunction: one group in which dysfunction is associated with, or related to, airways reactivity, and one group in which dysfunction is related to other factors.