Cerebral toxoplasmosis is an opportunistic infection that, by itself, is difficult to differentiate from cerebral neoplasms by conventional neuroimaging. It rarely occurs concurrently in patients with a primary brain tumor but when it does, it makes diagnosis and management more difficult. This is a case of a 28-year-old female, diagnosed with a right frontal pleomorphic xanthoastrocytoma with several recurrences, treated with surgery, radiation, and chemotherapy. Three years from diagnosis, the patient was readmitted for generalized body weakness, fever, and a decrease in sensorium. A repeat cranial magnetic resonance imaging showed multiple enhancing lesions in both cerebral hemispheres and in the posterior fossa. Serum toxoplasma IgM and IgG antibody titers were elevated. Single-photon emission computerized tomography (SPECT) with thallium-201 did not show increased tracer uptake in these lesions, favoring toxoplasmosis over tumor recurrence. The patient was treated with trimethoprim-sulfamethoxazole with significant improvement. This is a rare account of cerebral toxoplasmosis arising in the setting of astrocytoma. This is also the first case report to demonstrate the value of thallium-201 SPECT in differentiating central nervous system infection from tumor recurrence, which is pivotal in management. More studies exploring the use of thallium-201 SPECT in distinguishing central nervous system infections from glioma and other malignant tumors should be undertaken to maximize this imaging modality in neuro-oncology practice.