Acute lung injury (ALI) carries a high risk of mortality but has no established pharmacologic therapy. We previously found that experimental ALI occurs through natural killer (NK) cell NKG2D receptor activation and that the cognate human ligand, MICB, was associated with ALI after transplantation. To investigate the association of a common missense variant, , with ALI. We assessed genotypes within two multicenter observational study cohorts at risk for ALI: primary graft dysfunction ( = 619) and acute respiratory distress syndrome ( = 1,376). Variant protein functional effects were determined in cultured and human samples. Recipients of -homozygous allografts had an 11.1% absolute risk reduction (95% confidence interval [CI], 3.2-19.4%) for severe primary graft dysfunction after lung transplantation and reduced risk for allograft failure (hazard ratio, 0.36; 95% CI, 0.13-0.98). In participants with sepsis, we observed 39% reduced odds of moderately or severely impaired oxygenation among -homozygous individuals (95% CI, 0.43-0.86). BAL NK cells were less frequent and less mature in participants with . Expression of missense variant protein MICB in cultured cells resulted in reduced surface MICB and reduced NKG2D ligation relative to wild-type MICB. Coculture of variant MICB cells with NK cells resulted in less NKG2D activation and less susceptibility to NK cell killing relative to the wild-type cells. These data support a role for MICB signaling through the NKG2D receptor in mediating ALI, suggesting a novel therapeutic approach.