Opportunistic CNS-infection represent a major threat to patients after organ transplantation due to the need for ongoing immunosuppression and belatacept is a novel CTL4A inhibitor, which is increasingly used for patients following cadaveric kidney transplantation. Among the CNS infections, intracranial Aspergillus is a particular challenge and poses difficulties for its insidious onset, a timely and accurate diagnosis, and its management due to high mortality rates. To this end we want to illustrate the management of this scenario as encountered in a 71-year-old female patient, who was admitted into our institution in June 2007 with speech difficulties and gait instability 1.5 years after cadaveric kidney transplantation. On imaging, both a mediastinal and left frontal mass were found. Radiographically guided sampling of the mediastinal mass and a stereotactic biopsy of the left frontal brain lesion revealed Aspergillus fumigatus. With modification of immunosuppression and directed antifungal therapy there was complete resolution of the chest lesion; the brain lesion initially responded well but later progressed in size. Surgical intervention via a left fronto-temporal craniotomy with intraoperative image guidance was performed for a gross total resection of the lesion. Twenty-four months from resection, she remains on voriconazole with no evidence of recurrence and complete neurologic recovery and preserved renal function.