Background: Riociguat in Patients with Symptomatic Pulmonary Hypertension associated with Idiopathic Interstitial Pneumonias (RISE-IIP), a randomized, controlled, phase 2b trial of riociguat for pulmonary hypertension associated with idiopathic interstitial pneumonia, was terminated early due to increased mortality in riociguat-treated patients. Baseline characteristics of enrolled patients demonstrated a low diffusing capacity of the lung for carbon monoxide (DLCO) with preserved lung volumes at baseline, suggesting the presence of combined pulmonary fibrosis and emphysema (CPFE) in some patients. This post hoc analysis of RISE-IIP was undertaken to explore lung morphology, assessed by high-resolution computed tomography, and associated clinical outcomes. Methods: Available baseline/pre-baseline high-resolution computed tomography scans were reviewed centrally by 2 radiologists. The extent of emphysema and fibrosis was retrospectively scored and combined to provide the total CPFE score. Results: Data were available for 65/147 patients (44%), including 15/27 fatal cases (56%). Of these, 41/65 patients (63%) had CPFE. Mortality was higher in patients with CPFE (12/41; 29%) than those without (3/24; 13%). Fourteen patients with CPFE had emphysema > fibrosis (4 died). No relationship was observed between CPFE score, survival status, and treatment assignment. A low DLCO, short 6-min walking distance, and high forced vital capacity:DLCO ratio at baseline also appeared to be risk factors for mortality. Conclusions: High parenchymal lung disease burden and the presence of more emphysema than fibrosis might have predisposed patients with pulmonary hypertension associated with idiopathic interstitial pneumonia to poor outcomes in RISE-IIP. Future studies of therapy for group 3 pulmonary hypertension should include centrally adjudicated imaging for morphologic phenotyping and disease burden evaluation during screening. © 2021 The Authors, Ikaria Sanofi Inova Health System Roche University of Texas Southwestern Medical Center Gilead Sciences AstraZeneca Boehringer Ingelheim, BI Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, SNF United Therapeutics Corporation Merck Sharp and Dohme, MSD Novartis Sunovion Actelion Pharmaceuticals Pfizer National Institutes of Health, NIH GlaxoSmithKline, GSK National Heart, Lung, and Blood Institute, NHLBI Lunge Zürich Bayer Merck Sharp and Dohme, MSD, The authors have reported to the Journal of Heart and Lung Transplantation the following: S. D. Nathan reports consultation fees and Inova Fairfax Hospital receiving research funding for work pertaining to the RISE-IIP study from Bayer AG. V. Cottin reports grants from Actelion, Boehringer Ingelheim, GSK, Pfizer, and Roche, and personal fees from Bayer AG, Biogen Idec, Boehringer Ingelheim, Gilead, GSK, Intermune, Merck Sharp & Dohme, Novartis, Pfizer, Roche, and Sanofi. J. Behr reports receiving personal fees from Actelion, Bayer AG, Biogen, BMS, Boehringer Ingelheim, Galapagos, and Roche for consulting and lectures. M. M. Hoeper reports consultancy fees from Actelion, Bayer AG, and Pfizer, and personal fees from Actelion, Bayer AG, Pfizer, and Merck Sharp & Dohme. F. J. Martinez reports grants from National Institutes of Health and National Heart, Lung and Blood Institute, and support from Academic CME, Amgen, Annenberg, AstraZeneca, ATS, Axon, Axon Communication, Biogen, Bioscale, Boehringer Ingelheim, California Society for Allergy and Immunology, Carden Jennings, Centocor, CME Incite, CSA Medical, Falco, Forest, Genentech, Genzyme, GSK, Gilead, Inova Health System, Haymarket Communications, Ikaria, Informa, Integritas, InThought, Ikaria/Bellerophon, Janssen, Johnson & Johnson, Kadmon, MedScape, Merck, Miller Medical, National Association for Continuing Education, Novartis, Nycomed/Takeda, Paradigm, Pearl, Peer Voice, Pfizer, Promedior, Roche, Spectrum Health System, St John's Hospital, St Mary's Hospital, Sunovion, Theravance, University of Texas Southwestern, Unity Biotechnology, UpToDate, Western Society of Allergy and Immunology, Vertex, and Veracyte. T. J. Corte reports grants and personal fees from Boehringer Ingelheim and Roche, grants from Bayer AG, Gilead, and Intermune, and personal fees from AstraZeneca. A. M. Keogh reports grants and personal fees from Bayer AG. H. Leuchte reports personal fees from Actelion, Bayer AG, GSK, Merck Sharp & Dohme, and Pfizer, and nonfinancial support from Bayer AG. N. Mogulkoc reports receiving personal fees from Boehringer Ingelheim, Roche, Actelion, Bayer AG, and Nobel for consulting and lectures. S. Ulrich reports personal fees from Actelion and Bayer AG, and grants from Swiss National Science Foundation, United Therapeutics, and Zurich Lung League. W. A. Wuyts reports grants from Boehringer Ingelheim, FWO Flanders, Roche, and National Institutes of Health. Z. Yao was an employee of Bayer AG during the conduct of the RISE-IIP study. J. Ley-Zaporozhan reports consultation fees from Bayer AG and Boehringer Ingelheim. U. G. Müller-Lisse reports no conflicts of interest. F-D. Scholle, G. Brüggenwerth, and S. Nikkho were employees of Bayer AG during the conduct of the RISE-IIP study. D. Busse was an employee of Chrestos Concept GmbH & Co. during the development of this manuscript. A. U. Wells reports personal fees from Bayer AG, Roche, and Boehringer Ingelheim., The RISE-IIP study was funded by Bayer AG, Berlin, Germany, and Merck Sharp & Dohme Corp. , a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. D.B. performed statistical analyses, funded by Bayer AG, Berlin, Germany.