OBJECTIVES: Prophylactic treatment of severe Haemophilia A (HA) with clotting factor concentrates became standard of care in many countries, however its cost-effectiveness (CE) is controversial. This research critically appraises current evidence on CE of prophylaxis compared to on-demand treatment in patients with severe HA. METHODS: CE studies were searched in MEDLINE and Centre for Research and Dissemination. Study quality was assessed with Consensus Health Economic Criteria List. Costs were indexed to Euros 2015. Incremental cost-effectiveness ratios (ICERs) were compared. RESULTS: Eight publications met the inclusion criteria. The studies dated from 1996 to 2013 and evaluated relevant ICERs in the U.S., U.K., Germany, Netherlands, Sweden, Italy and Canada. ICERs were expressed as costs per bleed avoided: €1,029 to €18,128; or per Quality Adjusted Life Year (QALY) gained: from cost-saving to €1,538,460. Five studies applied long-term modeling, whereof three were based on a modification of the same Markov model. Modeling studies reported CE of prophylaxis from cost-saving up to €80,566/QALY. Evaluations with a time horizon of six and one year calculated ICERs of €466,346 and €1,538,460/QALY respectively. The underlying clinical evidence was overall weak. Presentation of model validation and analysis of uncertainty around the clinical evidence were limited in the modeling studies. CONCLUSIONS: Cost-effectiveness studies comparing prophylaxis and on-demand treatment in severe HA report strikingly conflicting results, from cost-saving to not cost-effective at all. Modeling studies show more consistent outcomes and stay within, or approach the reimbursement thresholds common in Western economies. Following guidelines for health economic evaluations in chronic conditions, results obtained with short-term time horizon have to be interpreted with caution; model validation should be a part of long-term CE analyses. Prospective observational studies based on wide utilization of identically designed patient registries form a high potential for strengthening clinical and health economic evidence in haemophilia.