Solitary focal demyelination (SFD) in the brain is an uncommon and poorly understood disorder of uncertain etiology that may represent an intermediate entity between multiple sclerosis and acute disseminated encephalomyelitis. In a few reported cases of SFD, the patient was briefly noted to have a nonneurological malignancy. We studied two patients who had solitary focal lesions in the brain. Utilizing magnetic resonance imaging and tissue biopsy, we found the characteristics of the brain lesions in these two patients to be those of SFD. In our combined experience over the past 10 years, we have encountered no similar brain lesions at our medical center. We found it remarkable that both of these patients also had malignancy outside of the nervous system. One had a seminoma, and the other a lymphoma. We conclude that some cases of SFD in the brain may occur as a paraneoplastic disorder associated with nonneurological malignancies.