A fatal case of Scopulariopsis acremonium sinus infection in an allogeneic hematopoietic stem cell transplant patient is reported. Rapid vascular diffusion of the fungus to the major head vessels was observed, which led to subsequent repeated cerebral ischemia and death. The presence of hyphae in the right carotid wall might be considered an indirect sign of fungal blood diffusion in the absence of positive blood cultures. The infection developed during the course of prolonged voriconazole prophylaxis, which was found to be effective in the in vitro antifungal drug assay. This finding induced us to consider the capacity of this drug to reach infected paranasal sinuses, and the need in cases such as this of a combined systemic and local pharmacological therapy or a combined medical and surgical approach.