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Background Antimicrobial resistance in enteric or urinary E. coli might predispose invasive E. coli infection and bacteraemia. Nitrofurantoin resistance occurs in Methods To elucidate chromosomal and acquired genetic determinants of nitrofurantoin resistance in E. coli, we analysed whole-genome sequences of nine randomly selected nitrofurantoin-resistant UTI E. coli isolates from West London. We then performed targeted analysis of 12,412 E. coli genomes collected from across the UK and predicted nitrofurantoin susceptibility from identified genotypes. Results Using comparative genomics, we found known and novel point mutations or insertion sequences (ISs) in chromosomal genes encoding oxygen-insensitive nitroreductases NfsA and NfsB in the nine isolates. Most of these genetic alterations resulted in gene inactivation. We also identified the same kinds of mutations in NfsA, NfsB, and their associated enzyme RibE in a number of 12,412 E. coli genomes. We also observed homoplasic mutations in all these proteins. By contrast, multidrug efflux pump OqxAB, which confers resistance when horizontally transferred, was only encoded by one genome. Conclusions Chromosomal de novo mutations and ISs are main causes of nitrofurantoin resistance in UK E. coli. Prevalence of nitrofurantoin resistance should be monitored among urine, blood, and enteric isolates as nitrofurantoin exposure increases.