Objectives: Current antibiotic treatment guidelines on when to consider 3rd generation cephalosporin resistant Enterobacteriaceae (3GC-R EB) as a cause of infection have low specificity, thereby increasing unnecessary carbapenem use. Therefore, we aimed to develop new diagnostic scoring systems to direct initial carbapenem treatment to patients at risk of 3GC-R EB bacteraemia. Methods: A retrospective nested case-control study was performed that included patients ≥18 years from 8 Dutch hospitals in whom blood cultures were obtained and intravenous antibiotics were initiated. Patients with 3GC-R EB bacteraemia were each matched to four control infection episodes within the same hospital, based on blood culture date and onset location (community or hospital). Starting from 32 commonly described clinical risk factors available at infection onset, selection strategies were used to derive scoring systems for the probability of community- and hospital-onset 3GC-R EB bacteraemia. Results: Among 22,506 community-onset and 8,110 hospital-onset infections, respectively 90 (0.4%) and 82 (1.0%) were 3GC-R EB bacteraemias. As control populations, 360 community-onset and 328 hospital-onset infection episodes were included. The derived community-onset and hospital-onset scoring system consisted of 6 and 9 predictors, respectively, and both showed good discrimination with c-statistics of 0.807 and 0.842. Cutoffs for the scores could be chosen such that ~20% of patients would be eligible for empirical carbapenem treatment, which would capture ~70% of those with 3GC-R EB bacteraemia. Conclusions: These prediction rules for 3GC-R EB bacteraemia, specifically geared towards the initiation of empiric antibiotic treatment, may improve the balance between inappropriate antibiotics and carbapenem overuse.