Abstract Diphenhydramine, a common ingredient in over-the-counter medications, is often taken in overdose. Toxicity is usually limited to anticholinergic symptoms. However, because diphenhydramine also exhibits type IA sodium channel blockade, cardiac toxicity is also possible. Although it would be expected that, like other type IA toxicities, diphenhydramine-induced cardiotoxicity could be responsive to hypertonic sodium bicarbonate, this finding is largely unappreciated. We describe 3 cases of diphenhydramine-induced cardiac toxicity that were responsive to bicarbonate.