Background: Isovolemic anemia results in improved gas exchange in rabbits with normal lungs but in relatively poorer gas exchange in rabbits with whole-lung atelectasis. In the current study, the authors characterized the effects of hemodilution on gas exchange in a distinct model of diffuse lung injury: venous gas embolization. Methods: Twelve anesthetized rabbits were mechanically ventilated at a fixed rate and volume. Gas embolization was induced by continuous infusion of nitrogen via an internal jugular venous catheter, Serial hemodilution was performed in six rabbits by simultaneous withdrawal of blood and infusion of an equal volume of 6% hetastarch: six rabbits were followed as controls over time. Measurements included hemodynamic parameters and blood gases, ventilation-perfusion ((V) over dot(A)/(Q) over dot) distribution (multiple inert gas elimination technique), pulmonary blood now distribution (fluorescent microspheres), and expired nitric oxide (NO; chemoluminescence). Results: Venous gas embolization resulted in a decrease in partial pressure of arterial oxygen (Pa-O2) and an increase in partial pressure of arterial carbon dioxide (Pa-CO2), with markedly abnormal overall (V) over dot(A)/(Q) over dot distribution and a predominance of high (V) over dot/(Q) over dot areas. Pulmonary blood flow distribution was markedly left-skewed, with low-flow areas predominating. Hematocrit decreased from 30 +/- 1% to 11 +/- 1% (mean +/- SE) with hemodilution. The alveolar-arterial P-O2 (A-aP(O2)) difference decreased from 375 +/- 61 mmHg at 30% hematocrit to 218 +/- 12.8 mmHg at 15% hematocrit, but increased again (301 +/- 33 mmHg) at 11% hematocrit. In contrast, the A-aP(O2) difference increased over time in the control group (P < 0.05 between groups over time). Changes in Pa-O2 in both groups could be explained in large part by variations in intrapulmonary shunt and mixed venous oxygen saturation (Sv(O2)); however, the improvement in gas exchange with hemodilution was not fully explained by significant changes in (V) over dot(A)/(Q) over dot or pulmonary blood flow distributions, as quantitated by the coefficient of variation (CV), fractal dimension, and spatial correlation of blood flow. Expired NO increased with with gas embolization but did not change significantly with time or hemodilution. Conclusions: Isovolemic hemodilution results in improved oxygen exchange in rabbits with lung injury induced by gas embolization. The mechanism for this improvement is not clear.