Background: Pulmonary hypertension (PH) is common in interstitial lung disease (ILD). Since cardiopulmonary exercise testing (CPET) is useful in understanding the pathophysiology of respiratory disorders and can distinguish between ventilation and perfusion (V/Q) defects, it may have a role in the detection of PH in ILD. We evaluated whether CPET can detect PH through analysis of V/Q defects in ILD. Objectives: We aimed to use CPET to determine if there are changes in the ventilation and the activity pattern of mixed-expired carbon dioxide pressure (PECO2) and end-tidal carbon dioxide pressure (PetCO2) in ILD patients with and without PH. Methods: A retrospective chart review was done of all patients who received lung transplants at the Columbia University Medical Center between 2000 and 2011 with the diagnosis of ILD. CPETs were performed during the 2 years prior to transplantation; right heart catheterizations and pulmonary function tests were performed within 4 months of CPET. Results: The ILD patients with PH demonstrated significantly lower PetCO2 and PECO2 during certain levels of exercise with a distinctive activity pattern for PECO2/PetCO2. Conclusions: Evaluation of V/Q defects through the PECO2 and PetCO2 patterns on CPET in ILD patients can distinguish between patients with and without PH.