This study examined the effect of aerosol histamine on lung lymph in the awake sheep. Eleven sheep were chronically instrumented for measurement of lung lymph, lung mechanics, and vascular pressures. Aerosol histamine was given by use of a Collison nebulizer and delivered via a tracheostomy tube. Five breaths of a 30 mg/ml histamine solution caused lung lymph flow (QL) to increase from a base line of 5.5 +/- 0.5 (SE) ml/h to 14.3 +/- 1.5 (P less than 0.05) and the lymph-to-plasma protein concentration ratio (L/P) to increase from 0.63 +/- 0.02 to 0.72 +/- 0.02 (P less than 0.05). The concentration of aerosol histamine required to change QL by 30% (ED130QL) was determined by giving increasing concentrations of aerosol histamine every 15 min. The mean ED130QL was 22.2 mg/ml. The dose of histamine required to increase QL by 30% did not correlate (r = 0.04, n = 7) with the dose required to decrease dynamic compliance by 35%. The increase in QL lasted 100 +/- 19 min. Hourly exposure to five breaths of 30 mg/ml for 5 h caused a sustained increase in QL in two sheep and a waning effect in two sheep. The combination of aerosol histamine and elevated microvascular pressure (achieved by inflating a Foley catheter situated in the left atrium) caused changes in QL and L/P not totally consistent with the hypothesis that histamine increased pulmonary vascular permeability. Increased vascular permeability in the bronchial circulation was considered a likely explanation of the data.