Long-term therapy with low-dose aspirin (acetylsalicylic acid; ASA), 75-325 mg, is highly effective for the secondary prevention of cardiovascular (CV) events. For high-CV-risk patients to attain the full benefits of this therapy, it is important that treatment is continuous and that good compliance is maintained over the long term. We aimed to quantify the level of, and investigate the reasons for, patient-driven non-compliance and treatment discontinuation among patients taking low-dose ASA for the prevention of CV events. We therefore performed a systematic search of the PubMed, Embase, and Cochrane databases using the terms 'aspirin' AND 'patient compliance' OR 'withdrawal', with no restrictions on the start date and up to July 2008. A total of 32 studies, summarizing >144 800 patients, were selected from over 400 results for inclusion. Poor compliance (defined differently among the studies included) with low-dose ASA therapy ranged from approximately 10% to over 50%, and patient-initiated discontinuation of therapy occurred in up to 30% of patients. Common predictors of both non-compliance and treatment discontinuation were lower education level, female sex, or a history of depression, diabetes mellitus, or cigarette smoking. Adverse events were cited as the reason for low-dose ASA discontinuation in almost 50% of patients. The findings of this review suggest that poor compliance is common among patients receiving low-dose ASA therapy, placing them at substantial risk of CV events. By addressing barriers to compliance with low-dose ASA therapy, healthcare professionals can improve CV risk management for such patients.