OBJECTIVES: Health technology assessment (HTA) agencies generally prefer the submission of direct evidence when appraising new interventions; however, an absence of head-to-head trial data is relatively common and indirect comparison is often required to determine relative effectiveness. To inform future submissions, acceptance rates across six HTA agencies were compared between submissions presenting direct evidence (active-comparator studies) and submissions lacking direct evidence. METHODS: All single HTA appraisals from 2014 for NICE (England), SMC (Scotland), CADTH (Canada), PBAC (Australia), IQWIG (Germany), and HAS (France) were included in the analysis, including resubmissions. Multiple technology appraisals, vaccination programmes, requests for advice, and submissions where the clinical evidence base was not described were excluded. The recommendation, reasoning behind the recommendation, and type of evidence presented were extracted. Fisher’s exact test was used to test for statistical significance. RESULTS: In 2014, NICE accepted 92% (11/12) of all submissions presenting direct evidence versus 88% (7/8) of submissions lacking direct evidence, SMC accepted 79% (26/33) versus 87% (13/15), CADTH accepted 90% (9/10) versus 53% (10/19), PBAC accepted 50% (26/52) versus 82% (14/17), IQWIG accepted 48% (13/27) versus 13% (2/15), and HAS accepted 97% (42/43) versus 92% (35/38). A lack of direct evidence tended to be acceptable in cases where hard endpoints could be compared, and in disease areas with small patient numbers or a lack of therapeutic alternatives. Adjusted indirect comparisons were generally favoured over unadjusted comparisons, where presented. CONCLUSIONS: With the exception of IQWiG (p=0.025), acceptance rates for submissions reporting direct evidence were not significantly different to rates for submissions lacking direct evidence for each agency, although acceptance rates varied across HTA agencies. Single-arm or placebo-controlled trials continue to be viewed as acceptable clinical evidence by most HTA agencies when such study designs are justifiable, and when relative efficacy can be demonstrated through robust indirect comparison.