To determine whether histamine affects airway goblet cell secretion and, if so, whether cholinergic mechanism is involved, we studied guinea pig airways by a semiquantitative morphometric method. The goblet cell secretion was assessed in histologic sections of the tracheal mucosa stained with Alcian blue and periodic acid-Schiff (PAS) by determining the mucus score, which is inversely related to the magnitude of mucus discharge. Inhaled or intravenously administrated histamine dose dependently decreased the mucus score, an effect that was similarly observed in cartilaginous and muscular portions. Inhalation of the anticholinergic agent oxitropium bromide at doses of 1.5 micrograms and higher greatly attenuated the decrease in mucus score produced by intravenous histamine but not by inhaled histamine. Likewise, cutting of bilateral vagus nerves or atropine abolished intravenous histamine-induced goblet cell secretion. The response of the mucus score to inhaled histamine was abolished by cimetidine, whereas the response to intravenous histamine was reduced by mepyramine but not by cimetidine or thioperamide. These results suggest that inhaled histamine increases airway goblet secretion, probably by stimulating histamine H2-receptors on goblet cells, and that intravenous histamine produces a similar effect through a stimulation of histamine H1-receptor-mediated release of acetylcholine from cholinergic nerve terminals, presumably involving vagal reflex.