To identify factors associated with Escherichia coli meningitis (ECM) mortality in infants aged <3 months, the clinical, biological and bacterial characteristics of isolates from 99 cases of ECM were compared, including the phylogenetic group, multilocus sequence type, O serogroup and sequence O type (a combination of sequence type complex (STc) and O serogroup) and virulence genotype. All 99 isolates were susceptible to the initial antimicrobial treatment. The mortality rate (14%) was not influenced by term or post-natal age. Hypotension or seizures were the sole clinical predictive factors for fatal outcome (p <0.01), and abnormal initial trans-fontanellar ultrasound was associated with death (p 0.03). Seventy-seven isolates belonged to the common sequence O types (STc29(O1), STc29(O18), STc29(O45), STc301(O7), STc304(O16), STc697(O83), STc700(O1)) causing neonatal meningitis. None of the phylogenetic groups and none of the virulence determinants were distributed differently between survivors and non-survivors, except that the aerobactin gene (iucC) was less frequent in lethal isolates (94% vs. 71%, p 0.02). Isolates belonging to rare sequence O types were more likely to be lethal (OR 4.3, p 0.01), although they induced a lower level of bacteraemia than common sequence O types such as STc29(O18) and STc29(O45) in a neonatal rat model. These results suggest that unidentified human genetic risk-factors may be more important than strain virulence in predicting ECM mortality.