Streptococcus suis is a zoonotic pathogen that infects pigs and can cause severe human infections, including meningitis and sepsis. This study aimed to understand the molecular epidemiology of human S. suis infections in Europe. Researchers surveyed 7 reference laboratories and conducted a systematic review of scientific literature, identifying 236 cases of human S. suis infections. Whole-genome sequencing of 46 isolates and analysis of 28 publicly available genomes revealed that 87% of human infections were caused by clonal complex (CC) 1 isolates, with CC20, CC25, CC87, and CC94 also contributing. The emergence of diverse zoonotic clades and the severity of human infections support classifying S. suis as a notifiable disease. S. suis is classified into 29 serotypes, with serotype 2 being the most common cause of human infections, accounting for approximately 95% of cases. Serotype 14 accounts for about 4%. The study found that most infections were caused by serotype 2 isolates, which belong to the zoonotic lineage CC1. The study also identified CC20 isolates, which emerged from CC16 in the Netherlands after acquiring a serotype 2 capsule. The study found that human S. suis infections are underreported in Europe due to the lack of notifiability. The incidence of S. suis infections in Europe is likely underestimated, as the disease is not a notifiable condition. The study identified cases in several European countries, including Germany, Spain, and the Netherlands, which accounted for 48% of all cases. The study also found that the incidence of S. suis infections in the at-risk population in six countries ranged from 0.161 to 4.945 cases per 100,000 persons. The study also found that the presence of genes associated with zoonotic potential varied across lineages. Some genes, such as sly, mrp, and fhb, were more common in zoonotic isolates but were not essential for S. suis to infect humans. The study concluded that S. suis infections should be made notifiable in Europe to improve surveillance of emerging zoonotic lineages and evolutionary trends. The study was funded by the European Union Horizon 2020 grant 727966 (PIGSs).Streptococcus suis is a zoonotic pathogen that infects pigs and can cause severe human infections, including meningitis and sepsis. This study aimed to understand the molecular epidemiology of human S. suis infections in Europe. Researchers surveyed 7 reference laboratories and conducted a systematic review of scientific literature, identifying 236 cases of human S. suis infections. Whole-genome sequencing of 46 isolates and analysis of 28 publicly available genomes revealed that 87% of human infections were caused by clonal complex (CC) 1 isolates, with CC20, CC25, CC87, and CC94 also contributing. The emergence of diverse zoonotic clades and the severity of human infections support classifying S. suis as a notifiable disease. S. suis is classified into 29 serotypes, with serotype 2 being the most common cause of human infections, accounting for approximately 95% of cases. Serotype 14 accounts for about 4%. The study found that most infections were caused by serotype 2 isolates, which belong to the zoonotic lineage CC1. The study also identified CC20 isolates, which emerged from CC16 in the Netherlands after acquiring a serotype 2 capsule. The study found that human S. suis infections are underreported in Europe due to the lack of notifiability. The incidence of S. suis infections in Europe is likely underestimated, as the disease is not a notifiable condition. The study identified cases in several European countries, including Germany, Spain, and the Netherlands, which accounted for 48% of all cases. The study also found that the incidence of S. suis infections in the at-risk population in six countries ranged from 0.161 to 4.945 cases per 100,000 persons. The study also found that the presence of genes associated with zoonotic potential varied across lineages. Some genes, such as sly, mrp, and fhb, were more common in zoonotic isolates but were not essential for S. suis to infect humans. The study concluded that S. suis infections should be made notifiable in Europe to improve surveillance of emerging zoonotic lineages and evolutionary trends. The study was funded by the European Union Horizon 2020 grant 727966 (PIGSs).