The public health value of whole genome sequencing (WGS) for Shigella spp. in England has been limited by a lack of information on sexual identity and behavior. We combined WGS data with other data sources to better understand Shigella flexneri transmission in men who have sex with men (MSM). WGS data for all S. flexneri isolates referred to the national reference laboratory were linked to i) clinical and behavioral data collected in seven of 21 health regions in England using a standardized exposure questionnaire and, ii) national HIV surveillance data. We included 926 S. flexneri isolates, of which 43.0% (n = 398) fell phylogenetically within two domestically circulating clades associated with genotypic markers of azithromycin resistance. Approximately one third of isolates in these clades were from people living with HIV, primarily acquired through sex between men. 182 (19.7%) isolates had linked questionnaire data; 88% (84/95) of MSM isolates fell phylogenetically within the domestically circulating clades, while 92% (72/78) of isolates from other cases fell within lineages linked with travel to high-risk regions. There was no evidence of sustained transmission between networks of MSM and the wider community. MSM were more likely to be admitted to hospital and receive antimicrobials. Our study emphasizes the importance of sex between men as a major route of transmission for S. flexneri. Combined WGS, epidemiological and clinical data provide unique insights that can inform contact tracing, clinical management and the delivery of targeted prevention activities. Future studies should investigate why MSM experience more severe clinical outcomes. IMPORTANCE Within the last 2 decades there have been an increasing number of Shigella spp. outbreaks among men who have sex with men (MSM) worldwide. In 2015, Public Health England (PHE) introduced routine whole genome sequencing (WGS) for the national surveillance of Shigella spp. However, the lack of information on sexual identity and behavior has hindered interpretation. Our study illustrates the power of linking WGS data with epidemiological, behavioral, and clinical data. We provide unique population-level insights into different transmission networks that can inform the delivery of appropriate public health interventions and patient management. Furthermore, we describe and compare clinical characteristics and outcomes of S. flexneri infection in MSM and other exposure groups. We found that MSM were more likely to be admitted to hospital and receive antimicrobials, indicating that their infections were potentially more severe. The exact reasons for this are unclear and require further exploration.