This study was to investigate a better way to detect and differentiate primary, residual, recurrent nasopharyngeal carcinoma (NPC) lesions post-radiotherapy in patients with NPC by means of routine computed tomography (CT) in combination with Tc-sestamibi single photon emission computed tomography (Tc-MIBI SPECT). Forty-eight patients with histologically confirmed primary NPC underwent Tc-MIBI SPECT at the 3rd month before and after radiotherapy, and at the 6th month after radiotherapy. All patients had contemporaneous CT examinations. Histopathologic results and/or clinical follow-up data (over 18 months) were used as the golden standard for evaluating residual/recurrent lesions. The radioactive count ratio of nasopharynx to scalp was obtained as the MIBI uptake index (MUI). Receiver operating characteristic analysis was employed to define the cut-off value of MUI for malignancy. With MUI 2.15 as the cut-off point, the accuracy for detecting primary NPC was 94.12%. The mean MUI in the local-regional of the nasopharynx in such negative cases was 1.21±€0.12 at the 3rd month, while the mean MUI was higher in the other 15 patients with histologically confirmed recurrent/residual lesions (MUI=1.40€±€0.16, =4.71, <0.001). The optimal cut-off point of 1.33 of MUI was defined with 89.58% accuracy for differentiating residual/recurrent lesions from the benign process post radiotherapy, while CT evaluations showed an accuracy of 81.25%. A combination of CT and Tc-MIBI SPECT for 37 NPC patients with congruent results showed an accuracy of 97.30% for differentiating residual/recurrent NPC from benign lesions. Tc-MIBI SPECT plays a role in evaluating residual/recurrent lesions post-radiotherapy. The combination of CT and Tc-MIBI SPECT can give more accurate diagnosis in the follow-up of NPC.