We asked whether hypoxia and hypercapnia, singly or combined, affect the lung volume-dependent ventilatory inhibition [Hering-Breuer (HB) reflex] in newborn rats. Conscious rats 2, 5, and 8 days old were breathing in a flow plethysmograph. Mean lung volume was increased by applying a negative body surface pressure of 6 or 12 cmH2O. HB reflex was quantified as the inhibitory ratio (IR) of the apnea during the inflation expiratory time (TEinfl) to the control expiratory time (TEc), i.e., IR = TEinfl/TEc. In normoxia-normocapnia (control), IR with 6 cmH2O was approximately 8-12 at all ages and approximately doubled with inflation at 12 cmH2O. In hypoxia (HPX; 10% O2) or hypercapnia (HPCN; 3% CO2), IR decreased at 8 days, whereas it did not differ from the control value at 2 and 5 days. In HPX + HPCN, IR decreased at all ages. In HPX (at both 6- and 12-cmH2O inflations), in HPCN (6 cmH2O), or in HPX + HPCN (6 and 12 cmH2O), IR decreased significantly more at 8 days than at 2 days. Metabolic rate, simultaneously measured, decreased during HPX or HPX + HPCN by a similar amount at all ages. The ventilatory response to HPX or to HPCN was significantly more pronounced at 8 days than at 2 days. We conclude that, during the early postnatal development of the rat, HPX or HPCN, singly or combined, reduces the HB reflex inhibition in the oldest pups, with minimal or no effects in the youngest. These developmental differences cannot be explained by differences in metabolic drive on ventilation but are contributed to by differences in chemosensitivity.