Gram-negative bacteria infection is sometimes followed by septic shock. This serious health condition is caused by the segregation of the lipopolysaccharide (LPS) from bacterial membrane into the bloodstream. Due to bacterial resistance, new antibiotics are needed. Most of the active antibiotics possess bactericidal effect, but lack LPS neutralization properties to prevent or neutralize septic shock. Antimicrobial peptides are a new class of antibiotics not prone to bacterial resistance, because their main target is the membrane. It is difficult for bacteria to critically change their membrane composition without affecting its molecular processes. rBPI21 is a recombinant antimicrobial peptide developed from an antimicrobial protein produced in neutrophils, the bactericidal/permeability-increasing protein (BPI) that ended phase III clinical trials against meningitis with success, reducing serious complications, such as amputations. It interacts preferentially with LPS with high affinity and at the same time has bactericidal effect. Here, we gather evidence that the interaction of the rBPI21 with LPS is mainly electrostatic, first, followed by massive LPS aggregation, which is correlated with its clearance from the bloodstream. The molecular mechanism at membrane level includes the peptide interactions with negatively charged phospholipids that promote outer and inner membrane hemi(fusion). This perturbation is followed by membrane permeabilization.