The use of antibiotic therapy combining at least two drugs remains controversial in patients with severe sepsis and septic shock. Some studies have suggested an improvement in patients' outcome with combination therapy over monotherapy, especially in those patients with expected mortality exceeding 25%. Nevertheless, a recent large randomized multicentric clinical trial, comparing the effects of meropenem and moxifloxacin to meropenem alone on the occurrence of sepsis-related organ dysfunction, found no significant advantage for combination therapy. Also, mortality rates were similar at 28 days and at 90 days in both groups. Considering some opposite observations coming from other recent non-randomized studies, we aimed to discuss the raisons of these conflicting findings on antimicrobials combination in patients with severe sepsis and septic shock.