We studied the contribution of inter- and intraregional inhomogeneities of specific ventilation (delta V/Vo) from the rebreathing inert gas trace in microgravity and on Earth. The rebreathing tests were carried out by four astronauts before, during, and after the 10-day Spacelab D-2 mission. Starting from functional residual capacity, the rebreathing maneuver consisted of eight reinspirations from a bag filled with 1.8-2.2 liters of test gas mixtures containing approximately 5% argon. The rate of argon equilibration in the rebreathing bag, termed RBeq, was quantified by determining the logarithm of the actual minus the equilibrated argon concentrations normalized to the inspired minus the equilibrated argon concentrations. A compartmental model of the lung (S. Verbanck and M. Paiva. J. Appl. Physiol. 76: 445-454, 1994) was used to validate the method for determining RBeq and to simulate the influence of intra- and interregional delta V/Vo inhomogeneities on the RBeq curve. The comparison between the experimental Earth-based and microgravity RBeq curves and model simulations shows that gravity-independent delta V/Vo inhomogeneity is at least as large as gravity-dependent delta V/Vo inhomogeneity.