We report the case of a 32-year-old man receiving chemotherapeutics for an acute B-lymphoblastic leukemia who developed proven cerebral and pulmonary aspergillosis with . Because of progressive fungal disease with neurological deterioration despite adequate systemic antifungal therapy and surgical debridement, intracerebral administration of liposomal amphotericin B was initiated at 5 mg twice weekly. This led to improvement of the cerebral infection. Surgical debridement of a pleural empyema was necessary, and pleural trough level of isavuconazole was found to be subtherapeutic despite adequate blood trough levels, which led us to increase the dose of isavuconazole. We conclude that intralesional amphotericin B might be beneficial at 5 mg twice weekly in cerebral aspergillosis if systemic antifungals and surgical debridement fail. In empyema, measurement of pleural isavuconazole trough levels should be considered.