Interstitial lung abnormalities have been associated with lower 6-minute walk distance, diffusion capacity for carbon monoxide, and total lung capacity. However, to our knowledge, an association with mortality has not been previously investigated. To investigate whether interstitial lung abnormalities are associated with increased mortality. Prospective cohort studies of 2633 participants from the FHS (Framingham Heart Study; computed tomographic CT scans obtained September 2008-March 2011), 5320 from the AGES-Reykjavik Study (Age Gene/Environment Susceptibility; recruited January 2002-February 2006), 2068 from the COPDGene Study (Chronic Obstructive Pulmonary Disease; recruited November 2007-April 2010), and 1670 from ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints; between December 2005-December 2006). Interstitial lung abnormality status as determined by chest CT evaluation. All-cause mortality over an approximate 3- to 9-year median follow-up time. Cause-of-death information was also examined in the AGES-Reykjavik cohort. Interstitial lung abnormalities were present in 177 (7%) of the 2633 participants from FHS, 378 (7%) of 5320 from AGES-Reykjavik, 156 (8%) of 2068 from COPDGene, and in 157 (9%) of 1670 from ECLIPSE. Over median follow-up times of approximately 3 to 9 years, there were more deaths (and a greater absolute rate of mortality) among participants with interstitial lung abnormalities when compared with those who did not have interstitial lung abnormalities in the following cohorts: 7% vs 1% in FHS (6% difference 95% CI, 2% to 10%), 56% vs 33% in AGES-Reykjavik (23% difference 95% CI, 18% to 28%), and 11% vs 5% in ECLIPSE (6% difference 95% CI, 1% to 11%). After adjustment for covariates, interstitial lung abnormalities were associated with a higher risk of death in the FHS (hazard ratio HR, 2.7 95% CI, 1.1 to 6.5; P = .03), AGES-Reykjavik (HR, 1.3 95% CI, 1.2 to 1.4; P < .001), COPDGene (HR, 1.8 95% CI, 1.1 to 2.8; P = .01), and ECLIPSE (HR, 1.4 95% CI, 1.1 to 2.0; P = .02) cohorts. In the AGES-Reykjavik cohort, the higher rate of mortality could be explained by a higher rate of death due to respiratory disease, specifically pulmonary fibrosis. In 4 separate research cohorts, interstitial lung abnormalities were associated with a greater risk of all-cause mortality. The clinical implications of this association require further investigation.