The quantitative relationship between goblet cell number and airway transepithelial permeability to horseradish peroxidase (HRP) (molecular weight, approximately 40,000 daltons) was examined in the guinea pig. In animals administered 12 daily successive doses of 2.5 mg pilocarpine intraperitoneally, an increase in goblet cell population in the trachea correlated with higher plasma HRP concentrations of all 4 sampling times after intratracheal instillation of 1 mg HRP. Guinea pigs administered a single dose of pilocarpine and studied 1 h later showed a significantly higher plasma HRP concentration at 10 and at 15 min (p less than 0.025) as compared with saline control animals. The morphologic correlates of this enhanced early permeability to HRP after a single dose of pilocarpine appeared to be increased vesicular uptake and accelerated transit across the goblet cells. Our data suggest that pinocytotic vesicular uptake and transport of exogenous proteins in the secretory epithelial cells of the airways may be an important pathway for movement of large polar solutes across the epithelial barrier.