Acknowledgements: We gratefully acknowledge the engagement and willingness of all participants to share information critical to the investigation. We are grateful to the authors and laboratories that originated and submitted the genetic sequences released in GenBank. The acquisition of equipment associated with whole-genome sequencing used in this study (including the Illumina NextSeq 2000) was funded by the HERA (Human and Environmental Risk Assessment) project (Grant/2021/PHF/23776), supported by the European Commission through the European Centre for Disease Prevention and Control (ECDC), and partially funded by the GenomePT project (POCI-01-0145-FEDER-022184), supported by COMPETE 2020 (Operational Programme for Competitiveness and Internationalisation (POCI)), Lisboa Portugal Regional Operational Programme (Lisboa2020), Algarve Portugal Regional Operational Programme (CRESC Algarve2020) under the PORTUGAL 2020 Partnership Agreement through the European Regional Development Fund (ERDF), and by the Portuguese Science and Technology Foundation (FCT). This study was also supported by the ERINHA-Advance project (funded by the European Union’s Horizon 2020 Research & Innovation program, grant agreement no. 824061) and benefited from co-funding from the European Union’s Horizon 2020 Research and Innovation programme under grant agreement no. 773830 (One Health European Joint Programme), in particular by the co-funding of the post-doctoral fellowships of J.S.D. and V.M. and the development of INSaFLU. We also thank M. Pinheiro (iBiMED at the Universidade de Aveiro) for his continuous support in updating the INSaFLU platform and the Infraestrutura Nacional de Computação Distribuída (INCD) for providing computational resources for testing it. INCD was funded by the FCT and FEDER under the project 22153-01/SAICT/2016. M.P.D. is funded by the Gates Cambridge Scholarship (no. OPP1144). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. The GAT-Intendente team also thanks A. Vasques, L. Fortuna, J. Moreira, I. Correia and Á. Baginha.Pathogen genome sequencing during epidemics enhances our ability to identify and understand suspected clusters and investigate their relationships. Here, we combine genomic and epidemiological data of the 2022 mpox outbreak to better understand early viral spread, diversification and transmission dynamics. By sequencing 52% of the confirmed cases in Portugal, we identified the mpox virus sublineages with the highest impact on case numbers and fitted them into a global context, finding evidence that several international sublineages probably emerged or spread early in Portugal. We estimated a 62% infection reporting rate and that 1.3% of the population of men who have sex with men in Portugal were infected. We infer the critical role played by sexual networks and superspreader gatherings, such as sauna attendance, in the dissemination of mpox virus. Overall, our findings highlight genomic epidemiology as a tool for the real-time monitoring and control of mpox epidemics, and can guide future vaccine policy in a highly susceptible population
