A number of agents are now available for empirical antifungal treatment (EAFT) of patients with persistent fever and neutropenia. We carried out a study of efficacy of antifungal drugs to prevent breakthrough invasive aspergillosis by reviewing the medical records of all consecutive patients who received EAFT from November 2005 to February 2006. Patients' characteristics and the type, dose and duration of antifungal therapy were recorded. Breakthrough invasive fungal infections were documented according to the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) definition. Fifty-six episodes of persistent fever with neutropenia requiring EAFT were recorded among 49 patients. All patients received high-dose chemotherapy for acute myeloid leukaemia (51%), acute lymphoid leukaemia (12%), lymphoma (14%) or other haematologic conditions (22%). Fourteen (29%) and five (10%) patients were allogeneic and autologous haematopoietic stem cell transplant recipients, respectively. Caspofungin was prescribed initially in 40 episodes (71%), amphotericin B (AmB) desoxycholate and liposomal AmB being prescribed in six (10%) and ten (18%) episodes, respectively. Six patients were switched from liposomal AmB to caspofungin because of adverse events. The median duration of antifungal therapy was 9 days. During follow-up, six patients (12%) were diagnosed with invasive aspergillosis after a median of 8 days (range 3-16 days) of EAFT. Invasive aspergillosis breakthrough occurred in 6/46 (13%) caspofungin recipients and in 0/16 (0%) AmB recipients (OR 3.1, p 0.32). The observed high rate of invasive aspergillosis among caspofungin recipients requires further evaluation.