The role of endogenous opioids in the control of breathing is not yet well defined. Radioimmunoassays that measure beta-endorphin (BE) and met-enkephalin (MET) having recently become available, we decided to evaluate the possible relation between the blood levels of these two opioids and different hypercapnic and hypoxic ventilatory responses observed in a group of normal subjects. Ventilatory response to hypercapnia (n = 9) and to hypoxia (n = 7) were determined by classical rebreathing methods. A voluntary isocapnic normoxic hyperventilation test was used as a control. Basal levels of BE and MET did not correlate with the magnitude of the ventilatory response to either hypercapnia or hypoxia. Moreover, BE and MET levels measured repeatedly up to 30 min after each test did not change significantly. We conclude that circulating endogenous opioids do not play a role in the control of breathing in normal humans. These results do not rule out a possible role for these substances as locally released mediators.