Our knowledge of airways reactivity to inflammatory agonists is derived predominantly from tests dominated by large airway responsiveness. To determine directly, the histamine responsiveness of the smallest airways, eight normal and 11 asymptomatic asthmatic subjects were studied utilizing a wedged bronchoscope technique. A fiberoptic bronchoscope was wedged in the anterior segment of the right upper lobe and a double-lumen catheter was advanced through the working channel to its tip. With a constant flow of gas (5% CO₂ in air) through one lumen of the catheter, pressure at the tip of the bronchoscope was measured with the subject breath-holding at FRC. Peripheral airways resistance (Rp) was measured at baseline and after saline, histamine (10, 50, 100 mg / ml) and isoproterenol (2 mg / ml) challenge through the bronchoscope. Baseline Rp of asthmatics (0.041 ± 0.015 cm H₂O / ml / min; mean ± SE) was significantly greater than normal subjects (0.011 ± 0.003 cm H₂O / ml / min; p = 0.019). The log of the concentration of histamine that caused a 100% increase in peripheral airways response was greater in the normal subjects than in the asthmatic subjects (p = 0.0114) and correlated with whole lung responsiveness to histamine in asthmatics (r = 0.847, p < 0.05). Isoproterenol reversed completely the increase in Rp in normal subjects but not asthmatic subjects. The results of this study demonstrate that the resistance of the smallest peripheral airways, when measured directly, increased when challenged locally with histamine in both normal subjects and asthmatic subjects. However, the peripheral airways responsiveness was significantly enhanced in asthmatic subjects relative to normal controls.