Antimicrobial therapy of complicated skin and soft tissue infections is guided by microbiological samplings performed in the preoperative period or during surgery. Antimicrobial treatment plays only an adjuvant role, the most important part of therapy is based on surgery. Systemic and local diffusion of antibiotic agents is poor. Cutaneous diffusion of antibiotics is delayed and incomplete. The most commonly administered treatments are betalactams agents combined to anti-anaerobes drugs such as nitroimidazoles, adapted to the location of infection. Prolonged duration of therapy is usually proposed.