Stenotrophomonas maltophilia is an emerging pathogen implicated in an increasing number of severe pulmonary infections and nosocomial sepsis. We evaluated the influence of four different antibiotics on the bacterial count and LPS activity found in broth cultures of S. maltophilia. After 4 h ceftazidime (CTZ) decreased live bacteria but increased endotoxin activity, whilst isepamicin (ISE), tobramycin (TB), and polymyxin B (PB) reduced both of them. We also investigated the influence of the above mentioned antibiotics on the ability of S. maltophilia culture filtrates and S. maltophilia LPS, extracted in our laboratory, to stimulate sepsis mediators such as tumor necrosis factor a (TNF-a), interleukin 8 (IL-8), interleukin 10 (IL-10), Nitric Oxide (NO) and as bactericidal/permeability-increasing protein (BPI) in human whole blood. Our results demonstrated that both single polycationic antibiotics and the combination of two molecules are able to kill bacteria and neutralize released S. maltophilia LPS. Combination between beta-lactams and aminoglycosides is often able to reduce the pro-inflammatory effects of S. maltophilia culture filtrates.