Introduction: the purpose of this retrospective multicenter study was to assess whether the risk of developing bloodstream infections (BSI) due to carbapenem-resistant Klebsiella pneumoniae (CRKP) in colonized patients is influenced by the occurrence of BSI due to other pathogens. Methods: from January 2012 to March 2014, all patients with at least one rectal swab positive for CRKP and at least 30 days of previous hospital stay were included in the study. The primary outcome measure was CRKP BSI, defined as a time-to-event endpoint. The role of potential predictors was evaluated through univariable and multivariable Cox regression analyses, considering previous BSI as a time-dependent variable. Results: during the study period, 353 patients met the inclusion criteria. Thirty-seven developed a CRKP BSI (11%). A higher incidence of CRKP BSI was observed in presence rather than in absence of previous BSI. In the final multivariable model of risk factors for CRKP BSI, multisite colonization (hazard ratio HR 13.73, 95% confidence intervals CI 3.29–57.32, p  < 0.001), ICU stay (HR 3.14, 95% CI 1.19–8.31, p = 0.021), and previous BSI ( p = 0.026, with the overall effect being mainly due to Enterococcus spp. BSI vs absence of BSI, HR 6.62, 95% CI 2.11–20.79) were associated with the development of CRKP BSI, while an inverse association was observed for age (HR 0.98, 95% CI 0.95–1.00, p = 0.027). Conclusions: previous BSI due to other pathogens were associated with an increased risk of CRKP BSI that was independent of other factors in colonized patients with prolonged hospital exposure.