Voriconazole is a broad spectrum antifungal agent however ineffective against Mucor sp. It has proven to have a higher efficacy in the control of invasive aspergillosis when compared to amphotericin B. However, the prophylactic use of voriconazole has not yet been defined. Nevertheless, it has become an attractive option because of the broad spectrum, limited toxicity and possible oral administration of voriconazole. We report here four cases of mucormycosis (3 in 2003, 1 in 2004) that occured after prolonged use of voriconazole in hematologic patients. Patients 1 and 2 (23 and 34 years old, respectively) had relapsed acute myeloid leukemia, patient 3 (3 years old) had chronic myelomonocytic leukemia, and patient 4 (52 years old) had high-grade B cell lymphoma. All patients were severely immunosuppressed. Patient 1 had received a T cell depleted, haploidentical stem cell transplantation (SCT). Patients 2 and 3 had each received a matched unrelated allogeneic SCT complicated by subsequent acute and chronic graft versus host diseases. Patient 4 had been treated for 5 years with mycophenolate mofetil and steroids after a renal transplantation. All four patients received continuous treatment with the oral form of voriconazole for 7 to 30 weeks prior to the diagnosis of mucormycosis: three as primary prophylaxis and one for a bronchial aspergillosis. Mucormycosis was diagnosed 9 weeks after the lymphoma or between 27 and 33 weeks after SCT for the transplanted patients. Patients were subsequently treated with liposomal amphotericin B. Fever was the most common symptom, indicating an invasive infection in the 3 patients who died rapidly at 12, 13 and 45 days after the diagnosis. The surviving patient, an allogeneic SCT recipient, had a localized bronchial mucormycosis. No evidence of mucormycosis had been observed prior to the introduction of treatment with voriconazole beginning in October 2002. In addition, to date, mucormycosis has only been observed in patients that have had pre-exposure to voriconazole. Physicians should be mindful of the potential risk of invasive mucormycosis after prolonged use of voriconazole in immunocompromised hematologic patients. Moreover, the question of prophylactic use of voriconazole needs to be adressed further in randomized trials.