The necessity for extended medication-based thromboprophylaxis after hip/knee-replacement surgery (major orthopedic surgery) has been acknowledged in international guidelines. In this article, we review and critically appraise the literature regarding patients' nonadherence (NA) in outpatient thromboprophylaxis after major orthopedic surgery. We conducted a systematic literature review. All studies published since 1990 and that were found to report research about NA in outpatient thrombosis prophylaxis after major orthopedic surgery were included. Only six relevant contributions could be identified. All these studies dealt with parenteral low-molecular-weight heparins or fondaparinux prophylaxis. The extent of NA (defined as existing when a patient fails to take the prescribed medication on at least 1 day) ranged from 13 to 37%. In one large German survey, patients who were nonadherent missed between 38 and 43% of their outpatient low-molecular-weight heparin injections. Subjective factors can play a role in increasing NA; such factors include a lack of knowledge of or having no fear concerning thrombosis in general and a lack of specific knowledge regarding measures to prevent it, as well as a negative evaluation of injections as the form of therapy application. Waiting times between acute in-hospital treatment and admission to rehabilitation clinics, as well as abstention from stationary rehabilitation programs, form objective adherence barriers. Therefore, NA is a phenomenon influenced by subjective patient-related factors as well as objective, care-provision structural factors. Current trends in patient care (e.g., shorter hospital stays and lengthened ambulant care) are likely to increase both the number of nonadherent patients and the extent of NA, if the current state of knowledge proves an accurate predictor of the future. At present, it appears that between one and two of every five patients are not adherent when parenteral prophylaxis is used. Whether or not new oral anticoagulation alternatives will be capable of improving the situation remains open for future research.