OBJECTIVES: Shigella sonnei resistant to first-line antibiotics azithromycin and ciprofloxacin are on the rise globally. The aim of this study was to describe the epidemiology of MDR S. sonnei in Belgium and to identify origins and circulating clusters through WGS. METHODS: We undertook demographic, temporal and geographical analysis of 930 S. sonnei isolates submitted to the Belgian National Reference Centre for Salmonella and Shigella between 2017 and 2019. Phylogenetic analysis of WGS data, genotyping and identification of genetic markers of antimicrobial resistance was performed on 372 Belgian isolates submitted between 2013 and 2019. RESULTS: S. sonnei was identified in 75% (930/1253) of Belgian Shigella isolates submitted between 2017 and 2019. Overall, 7% (69/930) of isolates were resistant to ciprofloxacin alone, 6% (57/930) showed reduced susceptibility to azithromycin alone, and 24% (223/930) exhibited both. Men were at higher risk of carrying a double resistant S. sonnei strain, compared with women (risk ratio = 8.6, 95% CI = 5.4-13.9). Phylogenetic analysis revealed four independent Belgian clusters of persistently circulating MDR strains, associated with men who have sex with men (MSM) and of the same genotypes as previously described international MSM-related clades. Belgian isolates carried various incompatibility (Inc)-type plasmids, the SpA plasmid and ESBL genes. CONCLUSIONS: In Belgium, S. sonnei isolates from men are much more likely to be resistant to important first-line antibiotics than isolates from women. Multiple co-circulating MDR S. sonnei clusters of different genotypes were identified in the MSM community. Further studies on risk groups are needed for targeted prevention, improved clinical and public health management and antimicrobial stewardship in Belgium.