Introduction: During COVID-19 outbreaks, disproportionate use of antibiotics, high Intensive Care Units burden and longer in-hospital stays may have aggravated the emergency posed by carbapenem-resistant isolates. Therefore, we set out to determine whether the incidence of carbapenem-resistant isolates rose in a tertiary care center in Santa Fe, Argentina during the period with active cases of COVID-19. Material and methods: In this retrospectively designed analytic epidemiologic study, two periods were defined: Period 1 (without active cases of COVID-19) from September 2019 to August 2020 and Period 2 (starting at the onset of the first wave of COVID-19 in this Institution) from September 2020 to June 2021. All clinically relevant microbiological samples taken during these periods in the Internal Medicine, Surgical and Intensive Care Unit wards were included. The primary analysis of interest was the differential incidence between the two periods, overall and in the Intensive Care Units wards in particular. Results: 9,135 hospitalizations, 50,145 patient-days of analysis. 7,285 clinical samples were taken, with an overall positivity for carbapenem-resistant isolates of 12.1% (n=883). Overall carbapenem-resistant isolates incidence during Period 2 was 2.5 times higher than in Period 1 (2.52 vs 0.955/100 patient-days, p<0.001). Intensive Care Units’ carbapenem-resistant isolates incidence raised from 6.78 to 8.69/100 patient-days in Period 2 (p=0.006). Conclusions: We found alarming rates of carbapenem-resistant isolates in our center, 2.5 times higher in the period following the first wave of COVID-19. This rise was due to a higher amount of clinically relevant microbiological samples taken and to a higher carbapenem resistance among Enterobacteria and non-fermentative Gram-negative bacilli. To our knowledge, this is one of the few Latin-American reports on the effect of the COVID-19 pandemic on carbapenem-resistant isolates incidence.