Atypical enteropathogenic Escherichia coli (aEPEC) is an important emerging pathogen in industrialised and developing nations. Classical approaches to categorise clinical isolates of aEPEC have shown that they are heterogeneous for sequence type (ST), serotype and antibiotic resistance profiles. We have analysed 185 whole-genome sequences of aEPEC strains collected during the Global Enteric Multicenter Study (GEMS) from seven countries in Asia and Africa. We first compared the core aEPEC genomes with publically available E. coli genomes before investigating their accessory genomes to determine serotype and resistance profiles by in silico genotyping and phenotypic methods. Phylogenomic analysis revealed ten globally distributed clonal lineages of aEPEC that differed in the proportion of case and control isolates suggesting differences in pathogenicity. Clonal lineages were characterised by diversity in their serotypes and resistance profiles. Diversity in serotype was detected in most lineages suggesting recombination within the relevant genetic regions. Resistance profiles within clonal lineages varied, although extensive resistance to third-generation cephalosporins was detected across all lineages. Further, whilst no carbapenamase resistance was detected, extended spectrum beta-lactamase resistance was detected in several isolates from India and Pakistan suggesting a geographical link to resistance acquisition. Our data suggest that soft selective pressure may be acting on aEPEC to facilitate sub-structuring within clonal lineages, as seen in other bacterial species, such as Streptococcus pneumoniae. Epidemiological data including antibiotic usage at each GEMS site will be used to interrogate the patterns of resistance acquisition within the aEPEC isolates. This study will result in a deeper understanding of the evolution of multi-drug resistance in aEPEC and Enterobacteriaceae in general.