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Background: Global estimates suggest millions of deaths annually are associated with antimicrobial resistance (AMR) but these are generated from scarce data on the relative risk of death attributable to drug-resistant versus drug-sensitive infections., Methods: We examined all episodes of E. coli bloodstream infection in Ontario, Canada between 2017 and 2020, and measured 90 day mortality among those with resistant versus sensitive isolates for each of 8 commonly used antibiotic classes and a category of difficult to treat resistance (DTTR). We used multivariable logistic regression to calculate an adjusted odds of mortality associated with AMR, after accounting for patient demographics, comorbidities, and prior healthcare exposure., Findings: Among 14,548 eligible episodes of E. coli bloodstream infection, resistance was most common to aminopenicillins (46.8%), followed by first generation cephalosporins (38.8%), fluoroquinolones (26.5%), sulfonamides (24.1%), third generation cephalosporins (13.8%), aminoglycosides (11.7%), beta-lactam-beta-lactamase-inhibitors (9.1%) and carbapenems (0.2%). Only 18 (0.1%) episodes exhibited DTTR. For each antibiotic class, the unadjusted odds of mortality (OR) were higher among resistant isolates, but after accounting for patient characteristics the adjusted odds (aOR) of mortality were attenuated: aminopenicillins (OR 1.22, 95% CI 1.12-1.33; aOR 1.09, 95% CI 0.99-1.20), first generation cephalosporins (OR 1.24, 95% CI 1.14-1.35; aOR 1.07, 95% CI 0.97-1.18), third generation cephalosporins (OR 1.64, 95% CI 1.47-1.82; aOR 1.29, 95% CI 1.15-1.46), beta-lactam-beta-lactamase-inhibitors (OR 1.69, 95% CI 1.52-1.89, aOR 1.28, 95% CI 1.13-1.45), carbapenems (OR 3.11, 95% CI 1.52-6.34; aOR 2.06, 95% CI 0.91-4.66), sulfonamides (OR 1.19, 95% CI 1.07-1.31, aOR 1.06, 95% CI 0.95-1.18), fluoroquinolones (OR 1.49, 95% CI 1.36-1.64, aOR 1.16, 95% CI 1.05-1.29), aminoglycosides (OR 1.43, 95% CI 1.27-1.62; aOR 1.27, 95% CI 1.11-1.46), and DTTR (OR 3.71, 95% CI 1.46-9.41; aOR 2.58, 95% CI 0.87-7.66)., Interpretation: AMR is associated with substantial increased mortality among patients with E. coli bloodstream infection, particularly for resistance to classes commonly used as empiric treatment. Surveillance for AMR-associated mortality should incorporate adjustment for patient characteristics and prior healthcare utilization., Funding: This work was supported by a project grant from CIHR (grant number 159503). This study was also supported by ICES, which is funded by an annual grant from Ontario Ministry of Health and Long-Term Care (MOHLTC)., Competing Interests: We declare that we have no conflicts of interest., (Crown Copyright © 2022 Published by Elsevier Ltd.)