We carried out a prospective, randomized four-center study in nosocomial pneumonia to evaluate the clinical and microbiological efficacy and safety of different treatment regimens in adult intensive care patients. During the randomized treatment of 18 patients with late onset pneumonia, ciprofloxacin (CIP) was compared to ceftazidim plus gentamicin (CAZ/GM), outbreaks of Staphylococcus aureus infections occurred in center 1. This article reports the unexpected findings. In the CIP group six out of ten patients were superinfected or reinfected with ciprofloxacin-resistant pathogens at the follow-up on day 5 after treatment. Four out of these six patients were superinfected with methicillin-susceptible or methicillin-resistant S. aureus (MRSA). Four superinfected patients died with pneumonia during treatment or before the follow-up. In the CAZ/GM group one out of eight patients was superinfected with MRSA. One patient died with pneumonia during treatment. There was no problem with multiresistant S. aureus or MRSA before the study period in center 1. In conclusion, we observed outbreaks of S. aureus infections during the treatment of late onset pneumonia with ciprofloxacin, which were associated with a high mortality. These superinfections occurred in mechanically ventilated, postoperative cardiac surgical patients after 13 days in the intensive care unit (ICU). We recommend combining ciprofloxacin with an antibiotic agent active against gram-positive bacteria in ventilator-associated pneumonia after a prolonged ICU stay. Selective pressure of ciprofloxacin could have played a role in these superinfections.