This study aimed to identify factors that influence the selection of different approaches to prescribing levofloxacin (e.g., monotherapy vs. combined therapy, 12-h vs. 24-h interval) and the effect on mortality in the ICU. An observational, prospective, multicenter study was conducted. A logistic regression analysis was performed to identify factors associated with the prescription of levofloxacin in combined therapy and at a dose of 500 mg every 12 hours. In addition, a logistic regression analysis was conducted to determine the impact of the different prescribing methods on mortality in the ICU. The most frequently administered initial dose was 500 mg/24 h (48.5%) and 500 mg/12 h (48.3%). No factors were found to influence the choice of daily dose. A total of 49.7% of levofloxacin prescriptions were in combined therapy. Factors influencing the decision to prescribe a combined regimen included diagnosis of extra-ICU nosocomial infection (OR: 1.97; 95% CI: 1.13-3.42); severe sepsis (OR: 2.56; 95% CI: 1.66-3.94); septic shock (OR: 6.22; 95% CI: 3.54-10.9); and identification of the causative pathogen (OR: 1.99: 95% CI: 1.34-2.95). The mortality rate was 21.4% and the related factors were septic shock (OR: 3.09; 95% CI: 1.38-6.91); treatment failure (OR: 23.4; 95% CI: 12.3-44.6); and combined therapy (OR: 2.36; 95% CI: 1.21-4.59). The selection of the initial dose of levofloxacin was not influenced by any factor, as long as the antibiotic was given in combined therapy in patients in whom the cause of the infection had been identified, in patients with greater systemic response, and in nosocomial infection outside the ICU. The selection of combined therapy was associated with a worse prognosis.