Abstract Co-amoxiclav (amoxicillin and clavulanate) is a commonly used combination antibiotic, with resistance in Escherichia coli associated with increased mortality. The class A beta-lactamase bla TEM-1 is often carried by resistant E. coli but exhibits high phenotypic heterogeneity, complicating genotype-phenotype predictions. We curated a dataset of n = 377 diverse E. coli isolates where the only acquired beta-lactamase was bla TEM-1. We generated hybrid assemblies and co-amoxiclav minimum inhibitory concentrations (MICs), and bla TEM-1 qPCR expression data for a subset (n = 67/377). We first tested whether intrinsic expression of bla TEM-1 varied between E. coli lineages, for example, from regulatory system differences, which are challenging to genomically quantify. Using genotypic features, we built a hierarchical Bayesian model for bla TEM-1 expression, controlling for phylogeny. Expression varied across the phylogeny, with some lineages (phylogroups B1 and C, ST12) expressing bla TEM-1 more than others (phylogroups E and F, ST372). Next, we built a second model to predict isolate MIC from genotypic features, again controlling for phylogeny. Phylogeny alone shifted MIC past the clinical breakpoint in 19% (55/292) of isolates with greater-than-chance probability, mostly representing ST12, ST69 and ST127. A third causal model confirmed that phylogenetic influence on bla TEM-1 expression drove variation in MIC. We speculate that intergenic variation underlies this effect.