A bloodstream infection (BSI) is a severe ICU-acquired infection. A growing proportion is caused by multidrug-resistant bacteria (MDRB). COVID-19 was reported to be associated with a high rate of secondary infections. However, there is a lack of data on the relationship between COVID-19 and the incidence of MDRB ICU-acquired BSI. The aim of this study was to evaluate the relationship between COVID-19 and ICU-acquired BSI related to MDRB. This retrospective study was conducted in a single-center ICU during a one-year period. All adult patients admitted for more than 48 h were included. The cumulative incidence of ICU-acquired BSI related to MDRB was estimated using the Kalbfleisch and Prentice method. The association of COVID-19 status with the risk of ICU-acquired BSI related to MDRB was assessed using cause-specific Cox’s proportional hazard model. Among the 1320 patients included in the analysis, 497 (37.65%) had COVID-19. ICU-acquired BSI related to MDRB occurred in 50 patients (36 COVID patients (7%) and 14 non-COVID patients (1.6%)). Extended-spectrum beta-lactamase Enterobacteriacae (46%) and carbapenem-resistant Acinetobacter baumannii (30%) were the most commonly isolated MDRB. COVID-19 was significantly associated with a higher risk of MDRB ICU-acquired BSI (adjusted cHR 2.65 (1.25 to 5.59) for the whole study period). However, this relationship was only significant for the period starting at day 15 after ICU admission. ICU-acquired BSI related to MDRB was significantly associated with ICU mortality (HR (95%CI) 1.73 (1–3)), although COVID-19 had no significant impact on this association (p het 0.94). COVID-19 is significantly associated with an increased risk of ICU-acquired BSI related to MDRB, mainly during the period starting at day 15 after ICU admission.