OBJECTIVES Reasons provided by the health technology appraisal (HTA) agencies for the guidance issued vary across the board. Following interest from a previous ISPOR presentation, we sought to further investigate the reasons for recommendation/rejection between NICE, SMC, CADTH, and PBAC with a specific focus on disease-specific reasons. METHODS A previously developed database was updated with data from submissions appraised between 31 May and 31 December 2008 by NICE, SMC, CADTH, and PBAC, in England/Wales, Scotland, Canada, and Australia, respectively. Submissions with opposing decision outcomes were included and were categorised by disease based on the BNF (cardiovascular system, CNS, endocrine system, gastro-intestinal system, infections, malignant diseases and immunosuppression, musculoskeletal and joint diseases, nutrition and blood, obstetrics, gynaecology, and urinary tract disorders, respiratory system, and skin). Reasons for acceptance/rejection were analysed across the disease categories. RESULTS In total, 83 submissions were included for analysis. Across all HTAs, the most common rejection reasons for skin disease interventions included “not more effective than comparators” and “not cost-effective”; these reasons were demonstrated in 100% of the submissions for interventions relating to skin disorders. The most common rejection reasons in malignant diseases and immunosuppression included “not cost-effective” and “concerns over the economic model” (100% for both). The majority of the reasons for rejection were reported in 50% or less of the submissions per disease group. Of the recommended interventions, those for the treatment of skin disease were all “more effective than placebo and comparators” as well as having a lower cost. Interventions for infectious diseases and obstetrics, gynaecology, and urinary tract disorders demonstrated a wide range of reasons for rejection. CONCLUSIONS Sub-group analysis categorised by disease provides further insight into the primary reasons for rejection and recommendation across HTA bodies. Analysing trends within these submissions highlights potential obstacles for new interventions within a specific disease area.