This study aimed to assess the extent and nature of recent changes in the management of outpatient parenteral antimicrobial therapy (OPAT) in Italy. We reviewed our previously reported data from 1999 to 2003 and compared them with data from patients who received OPAT from 2005 to 2010. Data for 1175 patients who received OPAT were analysed. Skin and soft tissue infections (SSTIs) were the most common infection treated with OPAT in both time periods, but an increase in patients with SSTIs receiving OPAT was observed. By contrast, a decline over time of OPAT use was found for patients affected by pneumonia. Furthermore, ceftriaxone use declined, whereas teicoplanin increased over time. In conclusion, OPAT use has significantly changed over time in Italy.