This study prospectively assessed the value of Tl-201 and Tc-99m-sestamibi (MIBI) SPECT in monitoring disease regression/progression as compared with MRI findings in patients with nasopharyngeal carcinoma (NPC) having radiotherapy with or without chemotherapy. Methods: Eighteen patients (age range 15-76 yr, mean 45 yr) had consecutive SPECT imaging using a dual-head gamma camera after the injection of 111 MBq Tl-201 and 555 MBq MIBI before therapy and at 3 mo and 6 mo after completion of therapy. A total of 106 SPECT studies was correlated with contemporaneous MRI studies. Tumor-to-background ratios were obtained on coronal slices. Visually detectable lesions in the region of the nasopharynx and cervical lymph nodes were considered positive for residual disease. The gold standard for the presence of disease was the combination of repeat MRI scans, endoscopic examination and clinical evaluation performed 12-15 mo after completion of therapy. Results: MIBI-SPECT proved superior to both Tl-201 SPECT and MRI after 3 or 6 mo follow-up in predicting complete response. Accuracy rates in the detection of residual disease in the nasopharynx are 39%, 72% and 89% for MRI, Tl-201 and MIBI, respectively, for the 3-mo evaluation; 71%, 71% and 94% for MRI, Tl-201 and MIBI, respectively, for the 6-mo evaluation. Conclusion: MIBI SPECT could be used as a screening test in predicting response to therapy in patients with NPC.