Posaconazole has been recently approved for primary antifungal prophylaxis in patients with prolonged neutropenia after AML induction chemotherapy and patients with GVHD. We now present the first experience of the efficacy and safety of posaconazole during the early phase of post-allogeneic BMT (n=33; from June 2007), in comparison with itraconazole primary prophylaxis (n=16; up to May 2007). More patients receiving posaconazole were T-cell depleted (P=0.003). Groups were otherwise comparable in terms of age, sex, disease, neutrophil engraftment, incidence of GVHD, use of unrelated donors and type of conditioning. Safety data as well as the incidence of fever (84%) and persistent fever (27%) during the 100-day treatment period were comparable for both antifungal agents. Patients receiving posaconazole had a lower cumulative incidence of proven or probable invasive fungal disease, as defined by the European Organization for Research and Treatment of Cancer criteria (0 vs 12%; P=0.04), which associated with a higher probability of fungal-free survival (91 vs 56%; P=0.003) and an improved probability of OS (91 vs 63%; P=0.011) compared with patients receiving itraconazole. Our single-centre experience suggests that antifungal prophylaxis with posaconazole may lead to a better outcome than itraconazole for patients in the early high-risk neutropenic period after allogeneic BMT.