Whether critically ill human immunodeficiency virus (HIV)-infected patients are at risk of acquiring nosocomial infections and resistant or potentially resistant microorganisms (RPRMs) remains to be clarified. The aim was to compare the acquisition of RPRMs, infections and mortality in critically ill HIV-infected and non-infected patients. An observational, prospective cohort study of patients admitted to a medical intensive care unit (ICU) was undertaken. Swabbing of nares, pharynx and rectum, and culture of respiratory secretions were obtained within 48 h of admission and thrice weekly thereafter. Clinical samples were obtained as deemed necessary by the attending physician. Clinical variables, severity scores on admission and exposures during ICU stay were collected. Logistic regression was used to evaluate ICU mortality. Out of the 969 included patients, 64 (6.6%) were HIV-infected. These patients had a higher Acute Physiology and Chronic Health Evaluation (APACHE) II score on admission (19.5 ± 6.6 vs. 21.1 ± 5.4, p = 0.02), stayed longer in the care unit and were more exposed to several invasive devices and antibiotics. There were no differences in the rate of acquisition of RPRMs and the only difference in ICU-acquired infections was a significantly higher incidence of catheter-related bacteraemia (3% vs. 9%, p = 0.03). The ICU-related mortality was similar in both groups (14% vs. 16%, p = 0.70) and in HIV-infected patients, it tended to be associated with a lower CD4 cell count (p = 0.06). Despite a longer ICU stay, critically ill HIV-infected patients did not show a higher rate of RPRMs acquisition. The rate of ICU-acquired infection was similar between HIV-infected and non-infected patients, except for catheter-related bacteraemia, which was higher in the HIV-infected population. Mortality was similar in both groups.