Background: A substantial aspect of health literacy is the knowledge of prescribed medication. In chronic heart failure, incomplete intake of prescribed drugs (medication non-adherence) is inversely associated with clinical prognosis. Therefore, we assessed medication knowledge in a cohort of patients with decompensated heart failure at hospital admission and after discharge in a prospective, cross-sectional study. Methods: One hundred and eleven patients presenting at the emergency department with acute decompensated heart failure were included (mean age 78.4±9.2, 59% men) in the study. Patients’ medication knowledge was assessed during individual interviews at baseline, course of hospitalization, and 3 months after discharge. Individual responses were compared with the medical records of the referring general practitioner. Results: Median N-terminal prohormone of brain natriuretic peptide plasma concentration in the overall population at baseline was 4,208 pg/mL (2,023–7,101 pg/mL [interquartile range]), 20 patients died between the second and third interview. The number of prescribed drugs increased from 8±3 at baseline to 9±3 after 3 months. The majority of patients did not know the correct number of their drugs. Medication knowledge decreased continuously from baseline to the third interview. At baseline, 37% (n=41) of patients stated the correct number of drugs to be taken, whereas only 18% (n=16) knew the correct number 3 months after discharge (P=0.008). Knowledge was inversely related to N-terminal prohormone of brain natriuretic peptide levels. Conclusion: Medication knowledge of patients with acute decompensated heart failure is poor. Despite care in a university hospital, patients’ individual medication knowledge decreased after discharge. The study reveals an urgent need for better strategies to improve and promote the knowledge of prescribed medication in these very high-risk patients.