Whipple disease is a rare systemic bacterial infection characterized by migratory polyarthralgia and chronic diarrhea. In 5 to 20% of patients with Whipple disease, the infection may present initially with or eventually develop symptoms related to the central nervous system (CNS). Although CNS involvement is a known feature of systemic N Whipple disease, intracerebral mass lesions are uncommon. Mass lesions in these cases are typically deep seated and multifocal. Corticosubcortical regions are unusual sites of CNS involvement in cases of Whipple disease. In the present paper, the authors, describe the first case of Whipple disease to feature a single corticosubcortical solid frontoparietal mass lesion that displayed homogeneous contrast enhancement on neuroimaging and was associated with bone destruction of the calvaria. Although CNS involvement has been observed in the form of deep-seated mass lesions in cases of systemic Whipple disease, unusual manifestations should be kept in mind during diagnosis and follow-up review in these patients.