HTA reimbursement recommendations often result in different outcomes across countries despite the same evidence being appraised for a same technology. There is a need to understand the reasons for these differences.  OBJECTIVES To systematically compare HTA processes for a sample of orphan drugs across four countries (England, Scotland, Sweden, France): to identify the use and interpretation of the evidence appraised, and highlight differences across countries.  METHODS Ten orphan drug-indication pairs were selected and systematically compared using a previously validated framework. An exploratory sequential mixed methods design divided the research into two stages: (1) qualitative in-depth analysis of the decision-making processes; and (2) quantitative identification of agency-specific risk preferences and agreement levels across countries. RESULTS Differences at each step of the decision-making process were identified. The same pivotal trials were appraised but with varying levels of detail in reporting the clinical outcomes, explaining some of the reasons for differing HTA recommendations. Agency-specific risk preferences were identified through correspondence analysis as drivers of these decisions, further explaining some of these differences. Poor to moderate agreement in the interpretation of the evidence was measured using Cohen’s kappa scores. This reflected situations where the countries interpreted the same evidence differently and situations where differences in the handling of the same uncertainties were seen, including differences in the extent to which stakeholder input influenced a decision.  CONCLUSIONS This research systematically compared HTA processes in different countries, facilitating the understanding of these complex processes including how different HTA bodies conduct value assessments. It enabled to raise awareness around the reasons for differences across countries, and highlight areas for potential methodological improvements in HTA. Further application of this framework to other disease areas and countries is a way forward to improving the drivers of coverage decisions while better understanding the settings and limitations of HTA.