The recent report from Picard et al. regarding extraintestinal Escherichia coli infections provides new insights into the relationships between clonal origin, virulence factor repertoire, and virulence (1). That clonal origin was only secondarily associated with virulence in this study was suggested by the finding that although mouse lethality was more frequent overall among strains of phylogenetic group B2 than among other strains, lethality was proportional to the number of virulence traits present (other than aer and afa) and was similar among B2 and non-B2 strains after stratification according to virulence factor numbers (Table 1). Stepwise logistic regression analysis of the data in Table 1 of Picard et al.(1) showed that, when competing with the individual virulence factors, phylogenetic group B2 status was never the strongest predictor of lethality for any of the three lethality endpoints analyzed (data not shown). When the presence or absence of two or more non-aer non-afa virulence factors was entered as a single dichotomous variable into logistic regression analysis along with B2 status, the presence of multiple virulence factors accounted for almost all the observed lethality, with B2 status exhibiting a weak and marginally significant residual association with lethality for only one of the three lethality endpoints (Table 2). These observations suggest that the group B2 genomic background is not required for virulence, whereas specific virulence properties are. They further suggest that the association of phylogenetic group B2 with extraintestinal virulence is attributable to the abundance of virulence factors in this lineage rather than to some undefined quality of the B2 genomic background per se. This concept is consistent with the traditional “virulent clone” hypothesis (4). What remains unclear is why extraintestinal virulence factors are so selectively concentrated within group B2. The major competing hypotheses to explain this phenomenon include (i) the existence of a special compatibility between the B2 genome and virulence genes and (ii) chance and timing.