BackgroundAccess to evidence-based psychological treatment is a concern in many parts of the globe due to government-level financial constraints and patient-level barriers. Transdiagnostic cognitive behavioural therapy (tCBT) is an effective treatment approach that uses a single protocol for anxiety disorders which could enhance the dissemination of evidence-based psychotherapy. In a context of limited resources, the study of treatment moderators can allow to identify subgroups for which the cost-effectiveness of an intervention differs, information that could impact decision-making. So far, there has been no economic evaluation of tCBT for different subpopulations. The objectives of this study, using the net-benefit regression framework, were to explore clinical and sociodemographic factors as potential moderators of the cost-effectiveness of tCBT compared to treatment-as-usual (TAU).MethodsThis is a secondary data analysis of a pragmatic randomized controlled trial opposing tCBT added to TAU (n = 117) to TAU only (n = 114). Data on costs from the health system and the limited societal perspectives, as well as anxiety-free days, an effectiveness measure based on the Beck Anxiety Inventory, were collected over an 8-month time horizon and used to derive individual net-benefits. The net-benefit regression framework was used to assess moderators of the cost-effectiveness of tCBT + TAU as opposed to TAU alone. Variables of sociodemographic and clinical nature were assessed.ResultsResults showed that the number of comorbid anxiety disorders significantly moderated the cost-effectiveness of tCBT + TAU compared to TAU from the limited societal perspective.ConclusionsThe number of comorbid anxiety disorders was identified as a moderator affecting the cost-effectiveness of tCBT + TAU compared to TAU from the limited societal perspective. More research is needed to strengthen the case of tCBT from an economic standpoint for large-scale dissemination.Trial registrationClinicalTrials.gov: NCT02811458, 23/06/2016Supplementary InformationThe online version contains supplementary material available at 10.1186/s12913-023-09468-7.