In dispersed mucosal cells from guinea pig stomach, D-lysergic acid diethylamide (LSD) was a partial agonist with respect to histamine. LSD, like histamine, inhibited [3H]histamine binding and increased both cellular cyclic AMP and [14C]aminopyrine uptake by interacting with histamine H2-receptors on parietal cells. These processes were blocked by both histamine H1- and H2-antagonists and, thus, provide evidence that histamine H2-receptors on guinea pig parietal cells resemble those in brain tissue in that they interact with LSD as well as with both classes of histamine antagonists.