Healthcare-associated infections (HAIa) and antimicrobial resistance are expected to be the next threat to human health and are most frequent in people with severe acquired brain injury (SABI), who can be more easily colonized by multidrug-resistant organisms (MDROs). The study's aim is to investigate the impact of MDRO colonizations and infections on SABI rehabilitation outcomes. This retrospective observational study was performed in a tertiary referral specialized rehabilitation hospital. The main outcomes were the presence of carbapenemase-producing Enterobacteriaceae (CPE) colonization, type and timing of HAI and MDRO HAI, and the number of CPE transmissions. We included 48 patients, 31% carrying CPE on admission and 33% colonized during the hospitalization. A total of 101 HAI were identified in 40 patients, with an overall incidence of 10.5/1000 patient days. Some 37% of patients had at least one MDRO infection, with a MDRO infection incidence of 2.8/1000 patient days. The number of HAIs was significantly correlated with the length of stay (LOS) (r = 0.453, p = 0.001). A significant correlation was found between colonization and type of hospital room (p = 0.013). Complications and HAI significantly affected LOS. We suggest that CPE carriers might be at risk of HAI and worse outcomes compared with non-CPE carriers.