Pentamorphone is a novel, potent opiate with rapid onset and short duration of action that has been reported to produce analgesia with limited depression of ventilation. We quantified the effects of pentamorphone (0.08, 0.24, and 0.60 .mu.g/kg, IV) on ventilatory responses to hypercapnia and hypoxia in 12 healthy volunteers. Normoxic hypercapnia and isocapnic hypoxia were induced through a rebreathing method. During each test we recorded ventilation (.ovrhdot.VE), end tidal carbon dioxide tension (PETCO2), and arterial oxygen saturation (SO2) using a pulse oximeter. Using linear regression analysis of the relationships between .ovrhdot.VE and PCO2 during hypercapnia and .ovrhdot.VE and SO2 during hypoxia, we determined the slope (slope CO2) and intercept (.ovrhdot.V55), both at PCO2 55 mm Hg, and the slope (slope O2) and intercept (.ovrhdot.V80) at SO2 80%. Pentamorphone produced dose-related reductions in the ventilatory responses to both hypercapnia and hypoxia. Maximal depression occurred 15 min after injection of pentamorphone with all doses; the highest dose (0.60 .mu.g/kg) produced 48% and 53% reductions in slope CO2 and .ovrhdot.V55, and 42% and 22% reductions in slope O2 and .ovrhdot.V80, respectively, relative to parallel saline controls. The respiratory depressant actions of pentamorphone were short-lived, as all parameters returned to baseline levels within 45 min. Testing was continued for 180 min after injection, but no delayed ventilatory effects were detected, and minimal side effects were reported, even at the highest dose. The findings confirm previous reports that pentamorphone has limited ventilatory depressant effects in humans in doses that (in other studies) have been associated with clinically effective analgesia.