The intention of this prospective study was to compare the diagnostic potential of technetium-99m sestamibi (MIBI) and a novel radiotracer,99mTc-Tetrofosmin (Tetro), for the assessment of primary nasopharyngeal carcinoma (NPC) and the differentiation of residual disease from post-therapy changes. A total of 38 patients underwent MIBI and Tetro single-photon emission tomography (SPET) imaging at initial presentation (n=22) or following therapy (n=16). The findings were correlated with computed tomography or magnetic resonance imaging (MRI) on a site-by-site basis. Tumour/background (Tm/Bkg) ratios were obtained on coronal sections. Biopsy (nine patients) and/or 12- to 24-month clinical follow-up data were available in the post-therapy group. All primary disease sites were accurately detected by both imaging studies. Although there was no statistical difference between the two imaging techniques in the detection of primary disease, MIBI was superior to Tetro in the detection of regional lymph node metastases (sensitivity: 95% vs 79%). Tetro and MIBI SPET were true-positive in all patients (n=7) with proven residual/recurrent diseuse. In nine patients who had no evidence of residual/recurrent tumour, MRI was false-positive in five while Tetro and MIBI SPET were false-positive in two and three patients, respectively. Tm/Bkg ratios were ≤1.7 in all false-positive cases except one. Tetro, MIBI and MRI had specificities of 78%, 67% and 44%, and accuracies of 87.5%, 81% and 69%, respectively. The results of Tetro and of MIBI SPET were rot statistically different from one another with regard to the prediction of residual/recurrent or metastatic NPC.