A 39-year-old man with newly diagnosed human immunodeficiency virus (HIV) infection was admitted with right-sided weakness, right-sided vision loss and slurred speech, which worsened over several weeks. Brain imaging revealed bilateral intraparenchymal ring-enhancing lesions and enhancement of the right optic nerve. Serological findings were positive for venereal disease research laboratory test, whereas the cerebrospinal fluid venereal disease research laboratory test was nonreactive. Brain biopsy suggested a diagnosis of syphilitic cerebral gummata, and the patient’s improvement with penicillin and dexamethasone further supported this etiology. Syphilitic cerebral gummata have rarely been reported in patients with HIV infection. This patient demonstrates that cerebral gummata should be considered in the differential diagnosis in immunocompromised patients with characteristic brain masses, that HIV and syphilis often coexist with early neurosyphilis appearing more frequently in this patient population and that normal cerebrospinal fluid studies may not represent a true lack of syphilitic activity in HIV patients.