OBJECTIVES: Different health technology assessment (HTA) agencies have differing criteria for acceptance, leading to divergent appraisal outcomes even when the same clinical study base is presented. To inform future submissions, we compared acceptance rates across four HTA agencies and explored consistency between decisions, including any differences between disease areas. METHODS: All single HTA appraisals in 2015 from NICE, CADTH, PBAC, and IQWiG were included in the analysis, including resubmissions. Multiple technology appraisals, vaccines, and requests for advice were excluded. The recommendation, reasoning behind the recommendation, and disease area (classified by ICD10 code) were extracted. RESULTS: A total of 189 appraisals met the inclusion criteria: 49 for CADTH (80% with a favorable outcome), 59 for PBAC (61% favorable), 36 for NICE (83% favorable), and 45 for IQWiG (40% favorable). The greatest proportion of submissions were for neoplasms (n=39, 59% with a favorable outcome), endocrine/metabolic disorders (n=29, 52% favorable), infections (n=23, 96% favorable), and respiratory system disorders (n=16, 69% favorable). The highest consistency between agencies was observed for infectious disease drugs (reflecting positive reactions to new highly-effective HCV drugs), while the most inconsistency was observed between IQWiG and the other agencies for endocrine/metabolic disease drugs (reflecting IQWiG’s unfavorable assessments of new diabetes drugs due to failure to demonstrate benefit over the appropriate comparator). Only five treatments were compared within the same indication across all four agencies in 2015: 1 consistently unfavorable (apremilast for psorasis), 3 consistently favorable (though with variations in the restrictions placed – all for HCV medicines), and 1 inconsistent (secukinumab for psoriasis). CONCLUSIONS: Acceptance rates vary considerably between HTA agencies, and divergence in decisions appears to be influenced by disease area. Acceptance rates for IQWiG are on average lower than for other HTA agencies, most notably for diabetes drugs, reflecting the agency’s strict evidence-based medicine approach to assessments.