Nasal decolonization has a proven effect on the prevention of severe Staphylococcus aureus infections and the control of methicillin-resistant S. aureus (MRSA). However, rising rates of resistance to antibiotics highlight the need for new substances for nasal decolonization. LTX-109 is a broad-spectrum, fast-acting bactericidal antimicrobial drug for topical treatment, which causes membrane disruption and cell lysis. This mechanism of action is not associated with cross-resistance and has a low propensity for development of resistance. In the present study, persistent nasal MRSA and methicillin-sensitive S. aureus (MSSA) carriers were treated for 3 days with vehicle or with 1%, 2%, or 5% LTX-109. A significant effect on nasal decolonization was observed already after 2 days of LTX-109 treatment in subjects treated with 2% or 5% LTX-109 compared to vehicle (P < 0.0012 by Dunnett=s test). No safety issues were noted during the 9-week follow-up period. Minimal reversible epithelial lesions were observed in the nasal cavity. The systemic exposure was very low, with a maximum concentration of drug in plasma (C max ) at 1 to 2 h postdosing (3.72 to 11.7 ng/ml). One week after treatment initiation, LTX-109 was not detectable in any subject. Intranasal treatment of S. aureus with LTX-109 is safe and reduces the bacterial load already after a single day of treatment. Hence, LTX-109 has potential as a new and effective antimicrobial agent with a low propensity of resistance development that can prevent infections by MSSA/MRSA during hospitalization. (This study has been registered at ClinicalTrials.gov under registration no. NCT01158235.) N asal carriage of Staphylococcus aureus is considered a marker of extended skin carriage and colonization by S. aureus. The colonization is often asymptomatic, but most severe S. aureus infections are caused by endogenous strains from the patient (1-5).Persistent nasal colonization by S. aureus, including methicillin-resistant S. aureus (MRSA) strains, has shown to be a major risk factor for surgical-site (6) and renal dialysis (5, 7) infections. Such individuals have a substantially increased risk for S. aureus hospital-acquired infections (8), with up to as many as 11 to 22% of methicillin-sensitive and -resistant S. aureus carriers developing nosocomial infections during hospital admission (9). In addition, patients carrying S. aureus can be a source of transmission to noncarriers, which subsequently can lead to health care-related exogenous infections.The spread of S. aureus remains unquestionably a serious challenge in infection control in hospitals, and in an attempt to reduce the S. aureus infection rates, prevention programs aiming at decolonizing individual nasal S. aureus carriers have been implemented. The most well-established regimen recommended in several national guidelines (e.g., in the 1998 United Kingdom guideline and the upcoming U.S. CDC guideline) is using a combination of 5 to 7 days of treatment with nasal mupirocin ointment and chlorhexidine soap (4,5,(10)(11)(12...