Background: CILP-1 regulates myocardial fibrotic response and remodeling and was reported to indicate right ventricular dysfunction (RVD) in pulmonary hypertension (PH) and heart failure (HF). This study examines CILP-1 as a potential biomarker for RVD and prognosis in heart failure with reduced ejection fraction (HFrEF) patients on guideline-directed medical therapy. Methods: CILP-1 levels were measured in 610 HFrEF patients from a prospective registry with biobanking (2016–2022). Correlations with echocardiographic and hemodynamic data and its association with RVD and prognosis were analyzed. Results: The median age was 62 years (Q1–Q3: 52–72), 77.7% of patients were male, and the median NT-proBNP was 1810 pg/mL (Q1–Q3: 712–3962). CILP-1 levels increased with HF severity, as indicated by NT-proBNP and NYHA class (p < 0.0001, for both). CILP-1 showed a weak–moderate direct association with increased left ventricular filling pressures and its sequalae, i.e., backward failure (LA diameter rs = 0.15, p = 0.001; sPAP rs = 0.28, p = 0.010; RVF rs = 0.218, p < 0.0001), but not with cardiac index (CI) and systemic vascular resistance (SVR). CILP-1 trended as a risk factor for all-cause mortality (crude HR for 500 pg/mL increase: 1.03 (95%CI: 1.00–1.06), p = 0.053) but lost significance when it was adjusted for NT-proBNP (adj. HR: 1.00 (95%CI: 1.00–1.00), p = 0.770). No association with cardiovascular hospitalization was observed. Conclusions: CILP-1 correlates with HFrEF severity and may indicate an elevated risk for all-cause mortality, though it is not independent from NT-proBNP. Increased CILP-1 is associated with backward failure and RVD rather than forward failure. Whether CILP-1 release in this context is based on elevated pulmonary pressures or is specific to RVD needs to be further investigated.