Background Carbapenemase-producing (CP) Escherichia coli (CP- Ec) are a global public health threat. We aimed to describe the clinical and molecular epidemiology and outcomes of patients from several countries with CP- Ec isolates obtained from a prospective cohort. Methods Patients with CP- Ec were enrolled from 26 hospitals in 6 countries. Clinical data were collected, and isolates underwent whole-genome sequencing. Clinical and molecular features and outcomes associated with isolates with or without metallo-β-lactamases (MBLs) were compared. The primary outcome was desirability of outcome ranking (DOOR) at 30 days after the index culture. Results Of the 114 CP- Ec isolates in Consortium on resistance against carbapenems in Klebsiella and other Enterobacterales-2 (CRACKLE-2), 49 harbored an MBL, most commonly bla NDM-5 (38/49, 78%). Strong regional variations were noted with MBL- Ec predominantly found among patients in China (23/49). Clinically, MBL- Ec were more often from urine sources (49% vs 29%), less often met criteria for infection (39% vs 58%, P =.04), and had lower acuity of illness when compared with non–MBL- Ec. Among patients with infection, the probability of a better DOOR outcome for a randomly selected patient with MBL- Ec as compared with non–MBL- Ec was 62% (95% CI: 48.2–74.3%). Among infected patients, non–MBL- Ec had increased 30-day (26% vs 0%; P =.02) and 90-day (39% vs 0%; P =.001) mortality compared with MBL- Ec. Conclusions Emergence of CP- Ec was observed with important geographic variations. Bacterial characteristics, clinical presentations, and outcomes differed between MBL- Ec and non–MBL- Ec. Mortality was higher among non-MBL isolates, which were more frequently isolated from blood, but these findings may be confounded by regional variations. [ABSTRACT FROM AUTHOR]