Prosthetic joint infections (PJI) occur in 0.8–1.9 % of arthroplasties, but the absolute number is increasing because of the frequency of procedures. Two stage exchange is the most effective strategy, but failures are often described. Culture of perioperative tissues during removal of arthroplasty is a standard procedure but culture during second step is equally important to define a success or a failure. We retrospectively reviewed PJI treated with two stage-exchange from January 2011 and December 2012 at “Ospedale S. Maria Misericordia”, Albenga-Italy. The procedure calls for bacterial culture not only during first step but also during reimplantation. Antibiotic treatment is prolonged after reimplantation until the cultures availability. A failure was defined by persistence of infection for positive culture or reocurrence of infection during a follow up of at least 2 years in patients with negative cultures. Three positive cultures yielding phenotypically identical organisms, or a single specimen of a virulent microorganism (e.g. Staphylococcus aureus) were required to rule out false positive for contaminants. Patients with persistence of infection were treated for 3 months with antibiotics. 86 patients underwent the two stage treatment: 45 hip and 41 knee prosthesis. The average ESR before arthroplasty removal was 59 mm/ 1st h (range 5–120), the average CRP was 3.9 mg/dl (range 0.3 – 34). Coagulase-negative staphylococci were isolated in 31 cases, Staphylococcus aureus in 19, Streptococcus spp in 8 and enterococci in 4. Gram-negatives were isolated in 4 patients and polymicrobial infection in 6 patients. In 14 patients (16%) no pathogen was identified. A positive culture during reimplantation was documented in 11 (13%) cases: 8 coagulase-negative staphylococci, 2 Staphylococcus aureus, 1 Candida sp. All patients received 3 months of therapy after surgery and 6 of them were free of infection at 2 years of follow up after the end of treatment. Among the 75 patients with negative cultures, a relapse was documented in 2 (3%), after 5 and 24 months, respectively. These cases were treated with arthrodesis and 6 weeks antibiotic treatment, with resolution of infection but poor functional results. Overall the success rate of our strategy was 92% (79/86). In patients treated with two-stage exchange, the combination of cultures at reimplantation and antibiotic suppressive treatment for 3 months in presence of positive cultures, are associated with a high rate of success. Only a prolonged follow up can rule out a relapse and agree with a true resolution of infection.