Patients with brain damage, contrary to normals, exhibit a significant ventilatory undershoot when brief hypocapnic hypoxia is terminated abruptly by hyperoxia. This has been attributed to an impairment of activation of short-term potentiation, a brain stem mechanism promoting breathing stability. We hypothesized that in these patients theophylline, a drug that stabilizes breathing, may affect short-term potentiation. Eight stable patients with brain damage and 10 normal adults were studied. Activation of short-term potentiation was examined by brief exposure to hypoxia followed by hyperoxia after pretreatment with placebo or theophylline. Both in patients and normals at the end of hypoxia ventilation increased to a similar magnitude with and without theophylline. In normals independent of pre-treatment, when hypoxia was terminated abruptly by hyperoxia ventilation declined slowly to baseline without an undershoot, indicating activation of short term potentiation. In patients with placebo, ventilation upon switching to hyperoxia exhibited a significant undershoot. This undershoot was significantly attenuated by theophylline although, compared to normals, a slight hypoventilation was observed. We conclude that in patients with brain damage theophylline largely prevents the hyperoxic drop of ventilation, presumably by affecting the activation of short term potentiation. This may underlie the beneficial effect of theophylline on breathing stability.