Inter-country variability in access to orphan drugs across countries has been highlighted in a number of studies. Understanding the reasons driving coverage decisions is a way forward in identifying areas where HTA methods may be improved. OBJECTIVES: Objectives are three-fold: a) to establish a methodological framework enabling to systematically compare HTA processes across countries; b) to identify the criteria driving HTA recommendations for a sample of orphan drugs, and; c) to understand the reasons for diverging recommendations and propose ways to minimize these. METHODS: All common orphan drug-indication pairs appraised in six countries (England, Scotland, France, Sweden, Canada and Australia) between 2001 and 2012 were selected. Agreement levels in HTA outcomes between countries were measured using Cohen’s kappa scores. Thematic analysis, by creating an NVivo-9 coding manual, was conducted to systematically compare each compound. Reasons for diverging HTA outcomes were differentiated based on whether they are a consequence of country-specific considerations or of the HTA process, and ranked by frequency of occurrences. RESULTS: Fourteen orphan drug-indication pairs were retrieved. Agreement in HTA outcomes was poor (k = [-0.5; 0.3]). Eight drug-indication pairs appraised by at least four HTA bodies were analyzed, five of which received diverging outcomes. Preliminary results suggest that in four of five cases, reasons for diverging recommendations were a consequence of the HTA process. Examples of non-homogeneous assessments include: lack of appropriate primary endpoint, lack of long-term data, evidence not reflecting clinical practice, orphan status or unmet clinical need.   CONCLUSIONS: Preliminary results identify the criteria driving the assessments and reasons why they result in diverging HTA outcomes, enabling a better understanding of these processes by elucidating the expectations and value judgments from HTA bodies, particularly on the orphan status, and identifying areas where more consensus on what constitutes appropriate HTA methodologies is needed. Final results will quantify these criteria in a systematic manner.