INTRODUCTION: Rare disease treatments (RDTs) promise considerable patient benefit but the evidence to demonstrate their value in health technology assessment (HTA) is often limited. HTA outcomes for RDTs vary across countries and there are differences in how uncertainty is dealt with by HTA agencies. Yet, there is limited comparative research assessing how different HTA agencies consider issues affecting evidence quality and uncertainty in RDT appraisals. This protocol describes a systematic and consistent approach for data extraction from RDT appraisal documents produced to inform decisions by HTA agencies. By documenting data extraction rules transparently, we ensure reproducibility and reliability of analyses of the extracted data. METHODS AND ANALYSIS: We will select RDT appraisals issued by the National Institute for Health and Care Excellence (NICE) in England and the Federal Joint Committee (GBA) in Germany, using predefined inclusion criteria. We will extract data from appraisal documents in accordance with the rules set out in this protocol. We will analyse the extracted data to investigate how issues affecting evidence quality and uncertainty as documented in appraisals are considered, highlighting the similarities and differences between countries and identifying factors that are associated with HTA outcomes. ETHICS AND DISSEMINATION: This study was approved by the Ethics Committee of the London School of Hygiene & Tropical Medicine (reference number 29156). Study results will be submitted for publication in peer-reviewed journals.