OBJECTIVES: Determine the intra-tidal regional gas and blood volume distributions at different levels of atelectasis in experimental lung injury. Test the hypotheses that pulmonary aeration and blood volume matching is reduced during inspiration in the setting of minimal tidal recruitment/derecruitment and that this mismatching is an important determinant of hypoxemia. DESIGN: Preclinical study. SETTING: Research laboratory. SUBJECTS: Seven anesthetized pigs 28.7 kg (SD, 2.1 kg). INTERVENTIONS: All animals received a saline-lavage surfactant depletion lung injury model. Positive end-expiratory pressure was varied between 0 and 20 cm H2O to induce different levels of atelectasis. MEASUREMENTS AND MAIN RESULTS: Dynamic dual-energy CT images of a juxtadiaphragmatic slice were obtained, gas and blood volume fractions within three gravitational regions calculated and normalized to lung tissue mass (normalized gas volume and normalized blood volume, respectively). Ventilatory conditions were grouped based upon the fractional atelectatic mass in expiration (< 20%, 20-40%, and ≥ 40%). Tidal recruitment/derecruitment with fractional atelectatic mass in expiration greater than or equal to 40% was less than 7% of lung mass. In this group, inspiration-related increase in normalized gas volume was greater in the nondependent (818 µL/g [95% CI, 729-908 µL/g]) than the dependent region (149 µL/g [120-178 µL/g]). Normalized blood volume decreased in inspiration in the nondependent region (29 µL/g [12-46 µL/g]) and increased in the dependent region (39 µL/g [30-48 µL/g]). Inspiration-related changes in normalized gas volume and normalized blood volume were negatively correlated in fractional atelectatic mass in expiration greater than or equal to 40% and 20-40% groups (r = 0.56 and 0.40), but not in fractional atelectatic mass in expiration less than 20% group (r = 0.01). Both the increase in normalized blood volume in the dependent region and fractional atelectatic mass in expiration negatively correlated with PaO2/FIO2 ratio (ρ = -0.77 and -0.93, respectively). CONCLUSIONS: In experimental atelectasis with minimal tidal recruitment/derecruitment, mechanical inspiratory breaths redistributed blood volume away from well-ventilated areas, worsening PaO2/FIO2.