Background/Objectives: Combined pulmonary fibrosis and emphysema (CPFE) is associated with poor outcomes. We investigated the association of antifibrotic therapy on patients with CPFE. Methods: This retrospective study included adult patients, older than 18 years, with a diagnosis of CPFE between 2015 and 2019 using TrinetX database. CPFE was defined as a diagnosis of pulmonary fibrosis (PF) and emphysema or chronic obstructive pulmonary disease. Propensity score matching was performed to compare baseline characteristics for CPFE patients on antifibrotic therapy (nintendanib and pirfenidone) with those not on antifibrotic therapy. The outcomes studied included all-cause mortality, major adverse cardiac event (MACE, [myocardial infarction, unstable angina]), hypoxic and hypercapnic respiratory failure, and stroke. These outcomes were compared at one-, three-, and five-year follow-ups. Results: Patients were divided into two cohorts: those on antifibrotic therapy (cohort 1, n = 861) and those without antifibrotic therapy (cohort 2, n = 861). Although not statistically significant, there was a trend towards increased mortality in cohort 1 at the 5-year follow-up (HR 1.14; CI 0.99–1.33). There was also an increased incidence of MI (HR 1.68; CI 0.88–1.47) and hypoxic respiratory failure (HR 1.17; CI 0.99–1.39). Notably, there was also a trend towards decreased incidence of stroke (HR 0.73; CI 0.51–1.05), and no difference in unstable angina (HR 0.94; CI 0.47–1.86) and hypercapnic respiratory failure (HR 0.99; CI 0.67–1.47). Conclusions: For patients with CFPE, antifibrotic use demonstrated a trend towards increased risk of mortality at 5-year follow-up, raising concerns for “sicker patient” bias. Prospective studies should be designed to include patients with CPFE and evaluate the benefits of antifibrotics.