Epidemiological studies suggest that bronchial hyper-responsiveness (BHR) and elevated levels of serum IgE are more frequently found in current smokers than in ex-smokers. Since elevated serum IgE is associated with BHR under both in vivo and in vitro conditions, we aimed to assess whether smoking affects BHR independently from IgE. Lung resection material was obtained from 27 current smokers and 11 non-smokers with low serum IgE (< 100 U/mL). Peripheral airways were cut into rings and incubated overnight in the presence (passively sensitized) or absence (non-sensitized) of serum containing IgE levels above 250 U/mL. Isometric contractile responses to histamine were assessed in the organ bath. Compared with non-smokers, isolated airways from smokers showed significantly increased responses to histamine (P < 0.05, ANOVA). Passive sensitization enhanced responses in both groups by about the same amount (P < 0.05, both). In patients with low serum IgE current smoking is associated with increased bronchial responsiveness to histamine in vitro, which can be further enhanced by passive sensitization. These findings suggest that both smoking and serum IgE contribute to non-specific airway hyper-responsiveness.