Enterobacter aerogenes was recently renamed Klebsiella aerogenes. This study aimed to identify differences in clinical characteristics, outcomes, and bacterial genetics among patients with K. aerogenes versus Enterobacter species bloodstream infections (BSI). We prospectively enrolled patients with K. aerogenes or Enterobacter cloacae complex (Ecc) BSI from 2002 to 2015. We performed whole-genome sequencing (WGS) and pan-genome analysis on all bacteria. Overall, 150 patients with K. aerogenes (46/150 [31%]) or Ecc (104/150 [69%]) BSI were enrolled. The two groups had similar baseline characteristics. Neither total in-hospital mortality (13/46 [28%] versus 22/104 [21%]; P = 0.3) nor attributable in-hospital mortality (9/46 [20%] versus 13/104 [12%]; P = 0.3) differed between patients with K. aerogenes versus Ecc BSI, respectively. However, poor clinical outcome (death before discharge, recurrent BSI, and/or BSI complication) was higher for K. aerogenes than Ecc BSI (32/46 [70%] versus 42/104 [40%]; P = 0.001). In a multivariable regression model, K. aerogenes BSI, relative to Ecc BSI, was predictive of poor clinical outcome (odds ratio 3.3; 95% confidence interval 1.4 to 8.1; P = 0.008). Pan-genome analysis revealed 983 genes in 323 genomic islands unique to K. aerogenes isolates, including putative virulence genes involved in iron acquisition (n = 67), fimbriae/pili/flagella production (n = 117), and metal homeostasis (n = 34). Antibiotic resistance was largely found in Ecc lineage 1, which had a higher rate of multidrug resistant phenotype (23/54 [43%]) relative to all other bacterial isolates (23/96 [24%]; P = 0.03). K. aerogenes BSI was associated with poor clinical outcomes relative to Ecc BSI. Putative virulence factors in K. aerogenes may account for these differences.