O2 and CO2 partial pressures in end-tidal gas (PA) and carotid artery blood (Pa) were measured during non-steady-state gas exchange in unanesthetized dogs. In 5 experiments (A), low O2 breathing in open circuit preceded prolonged rebreathing during maintained normoxia. In 6 experiments (B), steady-state hypoxia and hypercapnia were followed by rebreathing CO2 in hyperoxia which caused PAO2 to rise and then fall while PACO2 increased. Negative (Pa-PA)CO2, averaging -5 torr, were observed 10 sec after starting rebreathing in B and values between -1 and -2 torr were noted later in A and B. (PA-Pa)O2 showed considerable transient increases for 2 min in A and 20 sec in B. This behavior of (PA-Pa)O2 could be explained by a lung model with unequal distribution of alveolar ventilation and perfusion to alveolar volume. The negative (Pa-PA)CO2 values observed during rebreathing with rapidly increasing PACO2 were in part attributable to such unequal distribution effects, in part to lung-to-carotid artery transit time effects.