This study was concerned with the early effects on lung cells of infusion of 18 micrograms/kg histamine to the rabbit. For comparison purposes, other rabbits received a bolus of 0.4 micrograms/kg epinephrine. After administration, the lungs were immediately fixed by vascular perfusion of osmium tetroxide. In the group that received histamine, we observed selective alterations in the type I epithelial cells of the alveolar wall, consisting of localized thickening, increased number of cytoplasmic ribosomes, and homogeneity and increased electron density with reduction of the number of plasmalemmal vesicles. These alterations were quantitated; the vesicular load (no. of vesicles/cm2) was computed separately for each cell front of epithelial and endothelial cells. Epinephrine induced only edema in epithelial and endothelial cells, resulting in high electron lucency, thickening, and irregular cell profiles. We interpret the alterations seen in histamine-treated animals as reflecting uptake of histamine by the alveolar epithelium leading to an increased level of metabolic activity. Histamine induced no interstitial edema and no immediate reduction of capillary volume. The cellular edema related to epinephrine, a substance which is not taken up or metabolized by the lung, represented a form of cell injury.