The Escherichia coli lineage known as clonal complex 95 (CC95) is a cosmopolitan human-associated lineage responsible for a significant fraction of extra-intestinal infections of humans. Whole genome sequence data of 200 CC95 strains from various origins enabled determination of the CC95 pan genome. The core genome of CC95 was estimate to be 3134 genes and the balance of the genome was drawn from a variable gene pool of more than 14,000 genes. The pan genome analysis revealed that strains of the complex could be assigned to one of five subgroups that vary in their serotype, extra-intestinal virulence, virulence gene content, and antibiotic resistance gene profile. A total of 511 CC95 strains isolated from humans living in France, Australia and the USA were screened for their subgroup membership using a PCR-based method. The CC95 subgroups are non-randomly distributed with respect to their geographic origin. The relative frequency of the subgroups was shown to change through time, although the nature of the changes varies with continent. Strains of the subgroups are also non-randomly distributed with respect to source of isolation (blood, urine, faeces), and host sex . Collectively, the available evidence indicates that although strains belonging to CC95 may be cosmopolitan, human movement patterns have been insufficient to homogenise the distribution of the CC95 subgroups. Rather, the manner in which CC95 strains evolve appears to vary both spatially and temporally. Although CC95 strains appeared globally as pandemic, fine scale structure analysis shows epidemic patterns of the CC95 subgroups. Furthermore, the observation that the relative frequency of CC95 subgroups at a single locality has changed over time indicates that the relative fitness of the subgroups has changed.