We investigated the role of histamine H1- and H2-receptors in the control of airway function in six conscious sheep. In five of these, inhalation of histamine (combined H1- and H2-receptor stimulation) caused an increase in pulmonary resistance (RL) and functional residual capacity and had a variable effect on distribution of ventilation as measured by N2-clearance delay. Pretreatment with the H1-antagonist, chlorpheniramine, prevented these functional effects of histamine challenge, whereas pretreatment with the H2-antagonist, metiamide, potentiated the effects of histamine on RL and caused a uniform increase in N2-clearance delay. Pretreatment with both chlorpheniramine and metiamide prevented the effects of histamine on all parameters indicating effective blockade of H1- and H2-receptors at the dosages used. In one sheep, an increase in RL and N2-clearance delay in response to histamine was only observed after metiamide pretreatment. With or without pretreatment, histamine failed to alter the static pressure-volume curve of the lung. We conclude that in conscious sheep a) inhalation of histamine produces bronchoconstriction and pulmonary hyperinflation without changing lung elastic recoil, b) the observed effects of histamine are mediated by H1-receptors, and H2-receptors have a modulating role, and c) variable effects of histamine on RL and distribution of ventilation may be related to differences in the distribution of H1- and H2-receptors in central and peripheral airways.