OBJECTIVES: It has been suggested that ultra-rare diseases should be recognized as distinct from more prevalent rare diseases, but how drugs developed to treat ultra-rare diseases (DURDs) might be distinguished from drugs for ‘other’ (more common) rare diseases (DORDs) has not been examined. We compared the characteristics of DURDs to DORDs from an HTA perspective in submissions made to the CADTH Common Drug Review (CDR). METHODS: For each of 45 submissions for drugs for rare diseases (DRDs) made to the CADTH CDR between 2004 and 2014, we determined the molecular basis of the drug treatment, disease type, disease prevalence, study quality, annual treatment cost, type of reimbursement recommendation made by CADTH, and reasons for the recommendation. We calculated summary statistics after stratifying the data by subdividing the DRDs, based on disease prevalence, into DURDs (≤1 patient per 100,000 people) and DORDs (>1 to 50 patient per 100,000 people). RESULTS: DURDs and DORDs were similar in terms of the number of studies per submission, study quality, and reasons for recommendations. By contrast, growth in the number of submissions for DORDs exceeded that of DURDs; DURDs were almost exclusively biologic therapies, whereas DORDs include many small molecule-based therapies; sample sizes for DURD studies were smaller than those for DORDs; treatment costs for DURDS are substantially higher than those of DORDs; and there were relatively more negative versus positive reimbursement recommendations made for DURDs versus DORDs. CONCLUSIONS: These findings suggest that DURDs and DORDs could be viewed as distinct categories of DRDs from an HTA perspective. This suggests that applying the same HTA standards to DURDs and DORDs might be inappropriate and could account for the higher rate of rejection of DURDs. Adaptation of HTA processes to accommodate DURDs could ameliorate inequity in access to treatments for extremely rare conditions.