MRI is routinely performed to detect recurrence in patients with primary brain tumors, but it may not differentiate recurrent tumor from radiation-induced necrosis reliably. Thallium-201 single-photon emission computed tomography ((201)Tl-SPECT) might be useful in distinguishing between these two clinical entities. In a retrospective study (201)Tl-SPECT studies with corresponding MRI studies in 19 patients with clinical or radiological suspicion of high-grade tumor recurrence were reviewed. The diagnostic accuracies of both modalities were based on the subsequent histology or clinical course where biopsy was not performed. Post-scan histology was available in nine patients (43%) who underwent re-resection. The SPECT result determined management in six patients (29%). Post-SPECT survival was significantly better in patients with negative (201)Tl-SPECT studies compared to patients with positive studies (median survival 15+vs. 6 months) (p=0.04, log-rank test). The sensitivity and specificity of (201)Tl-SPECT in diagnosing tumor recurrence were 83% and 100%, respectively. (201)Tl-SPECT can accurately differentiate tumor recurrence from radiation necrosis in patients with high-grade gliomas and abnormal MRI findings post irradiation. This is reflected in a significantly longer post-scan survival time in patients with a negative (201)Tl-SPECT result.