Rationale:The relationship between interstitial lung abnormalities (ILA) and exercise capacity has not been comprehensively evaluated. Objectives: To assess the validity of the 6-minute walk test in subjects with ILA, and to examine the association between ILA and 6-minute walk distance (6MWD). Methods: Spearman correlation coefficients were used to assess the strength of the relationships between 6MWD and relevant measures of dyspnea, health-related quality of life, and pulmonary function in a cohort of 2,416 people who smoke from the COPDGene study. Unadjusted and adjusted linear and logistic regression models were used to assess the strength of the association between ILA and 6MWD. Measurements and Main Results: In all subjects, and in those with ILA, 6MWD in COPDGene was associated with relevant clinical and physiologic measures. The mean 6MWD in COPDGene subjects with ILA was 386 m (SD, 128 m), and 82% and 19% of subjects with ILA had 6MWDs less than or equal to 500 and 250 m, respectively. ILA was associated with a reduced 6MWD in univariate (230 m; 95% confidence interval, 250 to 210; P ¼ 0.004) and multivariate models (219 m; 95% confidence interval, 233 to 25; P ¼ 0.008). Compared with subjects without ILA, subjects with ILA had an 80% and 77% increase in their odds to have a walk distance limited to less than or equal to 500 and 250 m, respectively. Although these findings were dependent on ILA subtype, they were not limited to those with COPD. Conclusions: Our study demonstrates that ILA is associated with measurable decrements in the 6MWD of people who smoke. Clinical trial registered with www.clinicaltrials.gov (NCT 00608764).Keywords: six-minute walk distance; emphysema; interstitial lung disease; subclinical; idiopathic pulmonary fibrosis Subjects with interstitial lung abnormalities (ILA) have highresolution chest computed tomography (HRCT) features characteristic of patients with idiopathic interstitial pneumonia (IIP) (1) but have not been previously diagnosed with interstitial lung disease (ILD). Although our prior findings demonstrated that people who smoke with ILA have reduced total lung capacity and emphysema (2), it is not known if these findings merely represent radiologic abnormalities or if ILA results in measureable decrements in exercise capacity.The 6-minute walk test (6MWT) is a well-described and reproducible (3) measure of exercise capacity, disease severity, and mortality in patients with cardiopulmonary disease in general (4, 5), and IIPs in particular (6-8). We hypothesized that subjects with ILA, comparable with those with clinically apparent ILD, would have reductions in the distance they could walk in 6 minutes (6MWD). To test this hypothesis, we first assessed the validity of 6MWT in all COPDGene subjects and in analyses limited to those with ILA. Next, we evaluated the association between ILA and 6MWD in 2,416 COPDGene subjects. Based on our results we evaluated the association between ILA and previously described clinically relevant 6MWD thresholds (3, 9), the role of IL...