We have studied the effects on FEV1, of inhaled capsaicin in concentrations of 3 × 10−6 to 3 × 10−6 mg/ml and methacholine (1 to 16 mg/ml) in 15 heart-lung transplant (HLT) patients who had undergone recent transbronchial lung biopsy to determine the relationships in chronically denervated lungs between these different forms of airway hyperreactivity and inflammation. A total of 10 normal subjects and 17 asthmatic subjects were included for comparison. Capsaicin caused bronchodilation in eight HLT patients (FEV1 rising by 6.4 to 26.8%) and bronchoconstriction in two (fall in FEV1 of 7.2 and 7.6%). By contrast, seven asthmatic subjects developed bronchoconstriction after capsaicin (fall in FEV1 5.6 to 40.4%); the remaining 10 asthmatic subjects showed no response. Bronchial hyperresponsiveness to methacholine was most evident in the asthmatic subjects, but six HLT patients demonstrated a ≥ 20% fall in FEV1 with ≤ 8 mg/ml of methacholine. All normal subjects were nonresponsive to both agents, and all normal and asthmatic subjects, unlike HLT patients, coughed with capsaicin. No relationship existed between the methacholine and capsaicin responses. In the HLT patients neither form of airway responsiveness was related to the degree of inflammation seen on transbronchial lung biopsy. The results suggest that in normal subjects, although it provokes cough, inhaled capsaicin causes little airway narrowing. In HLT patients in whom both parasympathetic and sympathetic innervations are lost, capsaicin can cause modest bronchodilation, either by putative release of relaxant neuropeptides, such as vasoactive intestinal polypeptide (VIP), in retained postganglionic efferent nerves, or by direct relaxant effects on airway smooth muscle. By contrast, in asthmatic subjects capsaicin can cause bronchoconstriction, perhaps as a result of an imbalance between the effects of excitatory capsaicin on the inhibitory nonadrenergic, noncholinergic nervous system.