Background: Little is known regarding the prevalence or risk factors for non-comprehension and non-compliance with discharge instructions among older adults. Objectives: To quantify the prevalence of non-comprehension and non-compliance with discharge instructions and to identify associated patient characteristics. Research Design: Prospective cohort study. Subjects: 450 adults aged 65 years or older, admitted to medical and surgical units of a tertiary care facility in the USA and meeting inclusion criteria. Measures: We collected information on demographics, psycho-social factors, discharge diagnoses, and medications using surveys and patient medical records. Domains within discharge instructions included medications, follow-up appointments, diet, and exercise. At 5 days post-discharge, we assessed comprehension by asking patients about their discharge instructions, and compared responses to written instructions from medical charts. We assessed compliance among patients who understood their instructions. Results: Prevalence of non-comprehension was 5% for follow-up appointments, 27% for medications, 48% for exercise and 50% for diet recommendations. Age was associated with non-comprehension of medication (odds ratio (OR), 1.07; 95% CI, 1.04 to 1.12) and follow-up appointment (OR, 1.08; 95% CI, 1.00 to 1.17) instructions. Male sex was associated with non-comprehension of diet instructions (OR, 1.91; 95% CI, 1.10 to 3.31). Social isolation was associated with non-comprehension of exercise instructions (OR, 9.42; 95% CI, 1.50 to 59.11). Depression was associated with non-compliance with medication (OR, 2.29; 95% CI, 1.02 to 5.10) and diet instructions (OR, 3.30; 95% CI, 1.24 to 8.83). Conclusions: Non-comprehension of discharge instructions among older adults is prevalent, multi-factorial and varies by domain.