BACKGROUND Although diphenhydramine is frequently used to treat pruritus and nausea in patients who have received neuraxial opioids, there are no data regarding its effect on ventilatory control. We conducted the current study to evaluate the effects of diphenhydramine on hypercapnic and hypoxic ventilatory control in healthy volunteers. METHODS First, we measured the steady-state ventilatory response to carbon dioxide during hyperoxia with an end-tidal carbon dioxide tension of 46 or 54 mmHg (alternate subjects) in eight healthy volunteers. We then determined the hypoxic ventilatory response during isocapnic rebreathing at the same carbon dioxide tension. After a 10-min recovery period, we repeated the steady-state and hypoxic ventilatory response measurements at the other carbon dioxide tension (54 or 46 mmHg). Ten minutes after subjects received diphenhydramine 0.7 mg.kg-1 intravenously, we repeated this sequence of ventilatory measurements. RESULTS Under hyperoxic conditions (inspired oxygen fraction > 0.5) diphenhydramine did not affect the ventilatory response to hypercapnia. Similarly, at an end-tidal carbon dioxide tension of 46 mmHg, neither the slope nor the position of the hypoxic ventilatory response curve changed significantly after diphenhydramine. However, at an end-tidal carbon dioxide tension of 54 mmHg, the slope of the hypoxic ventilatory response increased from 1.28 +/- 0.33 to 2.13 +/- 0.61 l.min-1.%SpO2(-1) (mean +/- standard error), and VE at an arterial hemoglobin oxygen saturation of 90% increased from 31.2 +/- 3.1 to 43.1 +/- 5.4 l.min-1). CONCLUSIONS We conclude that although it did not affect the ventilatory response to carbon dioxide during hyperoxia or the ventilatory response to hypoxia at an end-tidal carbon dioxide tension of 46 mmHg diphenhydramine augmented the hypoxic response under conditions of hypercapnia in our young healthy volunteers. Although these findings may help to explain the apparent safety of diphenhydramine, they may not be applicable to debilitated patients or those who have received systemic or neuraxial ventilatory depressants.