Chronic Obstructive Pulmonary Disease (COPD) is a syndrome caused by damage to the lungs resulting in decreased pulmonary function and reduced structural integrity. Pulmonary function testing (PFT) is currently used to diagnose and stratify COPD into severity groups and chest computed tomography (CT) imaging is often used to assess structural changes in the lungs. We hypothesized that the combination of PFT and CT phenotypes would provide a more powerful tool for assessing underlying morphologic differences associated with pulmonary function in COPD than PFT alone. We used factor analysis of 26 variables to classify 8,157 participants recruited into the COPDGene cohort between January 2008 and June 2011 from 21 Clinical Centers across the United States. These factors were then used as predictors of all-cause mortality using Cox Proportional Hazards modeling. Five factors explained 80% of the covariance and represented domains for increased emphysema and decreased pulmonary function (Factor 1); airway disease and decreased pulmonary function (Factor 2); gas trapping (Factor 3); CT variability (Factor 4); and hyperinflation (Factor 5). Over 46,079 person-years of follow-up, Factors 1 through 4 were associated with mortality and there was a significant synergistic interaction between Factor 1 and Factor 2 on mortality. Considering CT measures along with PFT in the assessment of COPD can identify patients at particularly high risk for mortality.