ABSTRACT An emm 32.2 invasive group A streptococcus (iGAS) outbreak occurred in Liverpool from January 2010 to September 2012. This genotype had not previously been identified in Liverpool, but was responsible for 32% (14/44) of all iGAS cases reported during this time period. We performed a case-case comparison of emm 32.2 iGAS cases with non- emm 32.2 control iGAS cases identified in the Liverpool population over the same time period to assess patient risk factors for emm 32.2 iGAS infection. The emm 32.2 iGAS cases were confined to the adult population. We show that homelessness, intravenous drug use, and alcohol abuse predisposed patients to emm 32.2 iGAS disease; however, no obvious epidemiological linkage between the patients with emm 32.2 iGAS could be identified. Comparative whole-genome sequencing analysis of emm 32.2 iGAS and non- emm 32.2 control isolates was also performed to identify pathogen factors which might have driven the outbreak. We identified 19 genes, five of which had previously been implicated in virulence, which were present in all of the emm 32.2 iGAS isolates but not present in any of the non- emm 32.2 control isolates. We report that a novel emm 32.2 genotype emerged in Liverpool in 2010 and identified a specific subset of genes, which could have allowed this novel emm 32.2 genotype to persist in a disadvantaged population in the region over a 3-year period.