In comatose patients admitted to an ICU, particularly those with head injury, the incidence of early onset pneumonia is exceedingly high. We performed an open, prospective, randomized, and controlled clinical trial aiming at the reduction of the incidence of ventilator-associated pneumonia in head-injured patients and patients with stroke requiring mechanical ventilation. One hundred patients were included because of head injury or coma caused by medical stroke and with Glasgow coma scores < or = 12 and mechanical ventilation > 72 h. Patients eligible for the study (n = 50) received cefuroxime intravenously (two 1,500-mg doses 12 h apart after intubation) (the cefuroxime group) and 50 patients not receiving cefuroxime formed the control group. In the former group patients did not receive any other antibiotics before the end-point determination, whereas in the latter, 17 patients received prophylactic antibiotics as prescribed by the attending physician. The global incidence of microbiologically confirmed pneumonia was 37% (n = 37); 12 (24%) belonged to the cefuroxime group, and 25 (50%) belonged to the control group (p = 0.007). Early-onset pneumonia accounted for 70% of all the pneumonia episodes (n = 26), eight (67%) belonging to the cefuroxime group, and 18 (72%) belonging to the control group (p = 0.02). In the control group, four of 17 (23%) patients receiving prior antibiotics developed pneumonia, whereas 21 of 33 (64%) patients who did not receive antibiotics developed pneumonia (p = 0.016). The multivariate analysis revealed that the duration of mechanical ventilation (per each day) was an independent risk factor significantly associated to the development of pneumonia. Furthermore, the use of cefuroxime and/or prior antibiotics in the control group, before the pneumonia episode, had a protective effect against its development. No differences were found with regard to mortality and morbidity when comparing the study population with the control group. Nevertheless, when comparing patients with pneumonia (from both study and control groups) with those without it, there was a decrease in total hospital stay (35 +/- 13 versus 25 +/- 14 d, p = 0.048) and ICU stay (20 +/- 11 versus 11 +/- 7 d, p = 0.001). The study demonstrated that the administration of two single high doses 1,500 mg each of cefuroxime after the intubation of patients comatose because of head injury or medical stroke is an effective prophylactic strategy to decrease the incidence of ventilator-associated pneumonia.