© RSNA, 2018. Purpose: To determine if interstitial features at chest CT enhance the effect of emphysema on clinical disease severity in smokers without clinical pulmonary fibrosis. Materials and Methods: In this retrospective cohort study, an objective CT analysis tool was used to measure interstitial features (reticular changes, honeycombing, centrilobular nodules, linear scar, nodular changes, subpleural lines, and ground-glass opacities) and emphysema in 8266 participants in a study of chronic obstructive pulmonary disease (COPD) called COPDGene (recruited between October 2006 and January 2011). Additive differences in patients with emphysema with interstitial features and in those without interstitial features were analyzed by using t tests, multivariable linear regression, and Kaplan-Meier analysis. Multivariable linear and Cox regression were used to determine if interstitial features modified the effect of continuously measured emphysema on clinical measures of disease severity and mortality. Results: Compared with individuals with emphysema alone, those with emphysema and interstitial features had a higher percentage predicted forced expiratory volume in 1 second (absolute difference, 6.4%; P , .001), a lower percentage predicted diffusing capacity of lung for carbon monoxide (Dlco) (absolute difference, 7.4%; P = .034), a 0.019 higher right ventricular–to–left ventricular (RVLV) volume ratio (P = .029), a 43.2-m shorter 6-minute walk distance (6MWD) (P , .001), a 5.9-point higher St George’s Respiratory Questionnaire (SGRQ) score (P , .001), and 82% higher mortality (P , .001). In addition, interstitial features modified the effect of emphysema on percentage predicted Dlco, RVLV volume ratio, 6WMD, SGRQ score, and mortality (P for interaction, .05 for all). Conclusion: In smokers, the combined presence of interstitial features and emphysema was associated with worse clinical disease severity and higher mortality than was emphysema alone. In addition, interstitial features enhanced the deleterious effects of emphysema on clinical disease severity and mortality.