A significant cause of mortality in the intensive care unit (ICU) is multidrug-resistant (MDR) Gram-negative bacteria, such as MDR (MDR-AB) and carbapenemase-producing (KPC-Kp). The aim of the present study was to compare the clinical features, therapy, and outcome of patients who developed septic shock due to either MDR-AB or KPC-Kp. We retrospectively analyzed patients admitted to the ICU of a teaching hospital from November 2010 to December 2015 who developed septic shock due to MDR-AB or KPC-Kp infection. Data from 220 patients were analyzed: 128 patients (58.2%) were diagnosed with septic shock due to KPC-Kp, and 92 patients (41.8%) were diagnosed with septic shock due to MDR-AB. The 30-day mortality rate was significantly higher for the MDR-AB group than the KPC-Kp group (84.8% versus 44.5%, respectively; < 0.001). Steroid exposure and pneumonia were associated with MDR-AB infection, whereas hospitalization in the previous 90 days, primary bacteremia, and KPC-Kp colonization were associated with KPC-Kp infection. For patients with KPC-Kp infections, the use of ≥2 -active antibiotics as empirical or definitive therapy was associated with higher 30-day survival, while isolation of colistin-resistant strains was linked to mortality. Patients with MDR-AB infections, age >60 years, and a simplified acute physiology score II (SAPS II) of >45 points were associated with increased mortality rates. We concluded that septic shock due to MDR-AB infection is associated with very high mortality rates compared to those with septic shock due to KPC-Kp. Analysis of the clinical features of these critically ill patients might help physicians in choosing appropriate empirical antimicrobial therapy.