Acute lung injury (ALI) and severe sepsis are common critical illnesses associated with mobilization of bone marrow-derived cells into circulation. By identifying and determining these cells’ functional characteristics, unique prognostic biomarkers can be developed to help investigators understand mechanisms underlying the pathophysiology of these disorders. We previously demonstrated increased colony forming unit (CFU) ability of circulating peripheral blood mononuclear cells (PBMCs) from patients with ALI compared to healthy controls that also correlated with improved survival. Here we hypothesized that increased CFUs observed in ALI are associated with lung injury, and therefore ALI will result in an increased number of CFUs compared to patients with severe sepsis. To test this, blood was collected from 80 subjects (63 ALI and 17 severe sepsis) within 72 hours of diagnosis, and from 5 healthy controls. A CFU assay was performed on isolated PBMCs. Lung injury scores and need for mechanical ventilation were greater in ALI subjects than in severe sepsis (p<0.0001 for each). Colony-forming ability was highest in subjects with ALI compared to subjects with severe sepsis or controls (61 [13-104] versus 17 [3-34] versus 5 [2-13], p<0.0005). A trend towards improved survival was demonstrated in subjects with high (48) CFUs (p=0.06). No relationship between CFUs and mechanical ventilation was observed. Our findings suggest that increased colony-forming ability by PBMCs in ALI results from lung injury independent of sepsis and mechanical ventilation. Factors contributing to colony formation by PBMCs in ALI, and the role PBMCs play in its pathogenesis remain to be fully established.