Long-term adherence to prophylactic therapy is the key to successful prevention of bleeds in severe haemophilia. The present study aims to provide a systematic review of the literature on the determinants of adherence to prophylaxis in haemophilia. A literature search in the largest medical databases in Oct 2011 yielded 880 articles, which were reduced to 72 by further selection on title. Twenty-eight articles were excluded due to inclusion criteria. Full paper evaluation of 44 articles yielded five relevant articles that were critically appraised using the STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) statement and items extracted from the critical appraisal criteria for cohort studies (Dutch Cochrane Centre). After critical appraisal, 2/5 studies were considered as the best evidence available. The results of these two studies were further used in the synthesis for description of the determinants of adherence. This concerned a total of 245 subjects in all age groups. Data were collected using questionnaires and interviews. Motivators for a high adherence were as follows: experience of symptoms, a positive belief of necessity of treatment and a good relationship with the health care provider. Important barriers were defined as: infrequent or absence of symptoms and increasing age. Two high-quality studies were identified. Reported determinants of adherence to prophylaxis were age, symptoms, beliefs, and the relation with the health care provider. This information may provide a first step towards a strategy to promote adherence in haemophilia, with an important focus on age-specific interventions and patient education.