1. The effects of hypoxia, histamine-receptor agonist perfusion, and their combination on cardiac rhythm were studied in isolated rat hearts. 2. While hypoxia induced a high incidence of ventricular tachycardia or fibrillation, only a few preparations developed ventricular arrhythmias in response to perfusion with high concentration of histamine, 2-pyridylethylamine or impromidine. 3. The times of onset of hypoxia-induced ventricular arrhythmias were significantly shortened by perfusion with either histamine, 2-pyridylethylamine or impromidine. The accelerated occurrence of hypoxia-induced ventricular arrhythmias by histamine was significantly abolished by pretreatment with either diphenhydramine or cimetidine. 4. The results indicate that hypoxia and histamine can increase ventricular vulnerability of the rat heart to each other. It is also suggested that the arrhythmogenic actions of histamine in hypoxic rat hearts are mediated by both histamine H1-and H2-receptors.