Salmonella enterica serovar Enteritidis (S. Enteritidis) is a global cause of enterocolitis. However, distinct disease phenotypes have been observed in different settings: in high-income settings, S. Enteritidis causes epidemics of poultry-associated, self-limiting enterocolitis, whereas in sub-Saharan Africa it is a major cause of life-threatening invasive nontyphoidal Salmonella disease. Whole-genome sequence analysis of 675 isolates from 45 countries has identified three distinct epidemics of human disease: a global epidemic clade and two new clades of S. Enteritidis that are restricted geographically to distinct regions of Africa and have different phenotypes and genotypes. Additional clades and clusters demonstrated the wide diversity among S. Enteritidis worldwide.