This study was designed to compare the effectiveness of thallium-201 single-photon emission tomography (SPET) and conventional imaging, comprising computed tomography (CT) and magnetic resonance imaging (MRI), in the detection of residual/recurrent squamous cell carcinoma (SCC) of the oral cavity. Thirty-two patients with clinically suspected recurrent SCC of the oral cavity were recruited. All patients underwent (201)Tl SPET and CT or MRI within 2 weeks. The final diagnoses were based on the histology of the biopsy specimen. (201)Tl SPET and CT/MRI both accurately detected 17 of 18 residual/recurrent tumours. CT/MRI yielded eight false-positive studies, whereas (201)Tl SPET successfully excluded all tumours. The sensitivity, specificity, positive and negative predictive values and accuracy of (201)Tl SPET for the detection of recurrent oral SCC were 94%, 100%, 100%, 93% and 97%, respectively. The sensitivity, specificity, positive and negative predictive values and accuracy of CT/MRI for the detection of recurrent oral SCC were 94%, 43%, 68%, 86% and 72%, respectively. Thallium-201 SPET is more accurate than conventional imaging (CT or MRI) in differentiating residual/recurrent oral SCC from post-therapy changes.