Background: Decision-making on matters of public health and health policy is a deeply value-laden process. The World Health Organization (WHO)-INTEGRATE framework was proposed as a new evidence-to-decision (EtD) framework to support guideline development from a complexity perspective, notably in relation to public health and health system interventions, and with a foundation in WHO norms and values. This study was conducted as part of the development of the framework to assess its comprehensiveness and usefulness for public health and health policy decision-making. Methods: We conducted a qualitative study comprising nine key informant interviews (KIIs) with experts involved in WHO guideline development and four focus group discussions (FGDs) with a total of forty health decision-makers from Brazil, Germany, Nepal and Uganda. Transcripts were analyzed using MAXQDA12 and qualitative content analysis. Results: Most key informants and participants in the FGDs appreciated the framework for its relevance to real-world decision-making on four widely differing health topics. They praised its broad perspective and comprehensiveness with respect to new or expanded criteria, notably regarding societal implications, equity considerations, and acceptability. Some guideline developers questioned the value of the framework beyond current practice and were concerned with the complexity of applying such a broad range of criteria in guideline development processes. Participants made concrete suggestions for improving the wording and definitions of criteria as well as their grouping, for covering missing aspects, and for addressing overlap between criteria. Conclusion: The framework was well-received by health decision-makers as well as the developers of WHO guidelines and appears to capture all relevant considerations discussed in four distinct real-world decision processes that took place on four different continents. Guidance is needed on how to apply the framework in guideline processes that are both transparent and participatory. A set of suggestions for improvement provides a valuable starting point for advancing the framework towards version 2.0.