OBJECTIVES: There has been significant discussion on implementing a single Health Technology Assessment (HTA) process in Europe, in part because of the high level of variability among existing agencies. Agencies often disagree on the reimbursement decisions and on the economic and clinical conclusions. While disagreement on economic evaluations and reimbursement decisions can be explained by different agency remits and healthcare budgets, the driving factors of and justifications for clinical variability are currently unknown. This analysis examines drivers of clinical variability, specifically the clinical comparator, and uses case studies to explore instances where different comparators were used. METHODS: