Recognition of risk factors for hospital-acquired infections (HAI) in patients with COVID-19 is warranted. We aimed to describe factors associated with the development of HAI in patients with severe COVID-19. We conducted a retrospective cohort study including all adult patients admitted with severe COVID-19 between March 2020 and November 2020. The primary outcome was HAI development. Bivariate and multiple logistic regression models were constructed. Among 1540 patients, HAI occurred in 221 (14%). A total of 299 episodes of HAI were registered. The most common HAI were hospital-acquired/ventilation-associated pneumonia (173 episodes) and primary bloodstream infection (66 episodes). Death occurred in 387 (35%) patients and was more frequent in patients with HAI (38% vs. 23%, p < 0.01). Early mechanical ventilation (aOR 18.78, 95% CI 12.56–28.07), chronic kidney disease (aOR 3.41, 95% CI 1.4–8.27), use of corticosteroids (aOR 2.95, 95% CI 1.92–4.53) and tocilizumab (aOR 2.68, 95% CI 1.38–5.22), age ≥ 60 years (aOR 1.91, 95% CI 1.27–2.88), male sex (aOR 1.52, 95% CI 1.03–2.24), and obesity (aOR 1.49, 95% CI 1.03–2.15) were associated with HAI. In patients with severe COVID-19, mechanical ventilation within the first 24 h upon admission, chronic kidney disease, use of corticosteroids, use of tocilizumab, age ≥ 60 years, male sex, and obesity were associated with a higher risk of HAI.