Disorders of the cerebellum may present with motor, cognitive, behavioral and affective symptoms. There is a growing interest in developing neuroanatomical models of symptoms generation that involve the cerebellum and the cerebello-cortical connections. We describe an exciting first case report of successful use of Modafinil in an adult patient with post-operative posterior fossa syndrome. Following resection of a melanoma metastasis in the cerebellum the patient developed striking affective and behavioral symptoms in the form of withdrawn flat mood and disengagement. This neurobehavioral presentation severely impacted on his quality of life, independence, and ability to engage in the neuro-rehabilitative program. Pharmacological treatment with Modafinil ameliorated these emotional and behavioral aspects, and also fatigue. Treatment with Modafinil hence affected recovery and outcome for the patient. To our knowledge, this is the first description of a successful pharmacological intervention in an adult with post-surgical posterior fossa syndrome and negative neurobehavioral presentation. Our findings illustrate the variability of the presentation of post-operative posterior fossa syndrome in adults, and the importance of delivering targeted treatment to maximize the benefits of neurorehabilitation. The manuscript highlights the following points: 1. post-operative consequences currently under the wide umbrella of posterior fossa syndrome, can indeed manifest in adults; 2. a wide spectrum of neurobehavioral symptoms can occur, including a presentation with predominantly negative features; 3. the type of neurobehavioral presentation should guide the treatment choice with particular consideration of drugs that potentially modulate the cerebello-frontal connections; 4. Modafinil can be a candidate for effective treatment in presentations with predominantly negative behavioral symptoms.