Thallium-201 (Tl-201) single photon emission computed tomography (SPECT) is funded for evaluation of malignancy in Australia and may have utility for staging of non-small cell lung cancer (NSCLC) if CT results are equivocal. Fluorine-18 fluorodeoxyglucose (F-18 FDG) positron emission tomography (PET) is superior to CT for staging NSCLC but is more expensive and less widely available than Tl-201 SPECT. Therefore, these techniques were prospectively compared in 27 radical radiation therapy candidates. Patients were allocated a conventional, PET and Tl-201 stage. Tumour to background ratios (TBR) were recorded for the primary on both techniques. Metastatic disease was confirmed by surgical pathology, serial imaging or clinical follow up. Tumour to background ratios were consistently higher for FDG PET than Tl-201 SPECT (P < 0.0001). Positron emission tomography detected all known primary tumours but Tl-201 failed to image four primary tumours (15%). In 10 of 18 cases of discordance between PET and Tl-201 SPECT regarding stage, corroboration was available from pathology or disease progression. Positron emission tomography was shown to have a 100% positive predictive value, including all three patients with PET-detected distant metastases (P=0.002). Results indicate that PET is superior to Tl-201 SPECT scanning in the staging of NSCLC for radical radiation therapy, and that the low sensitivity for detection of local and metastatic disease is likely to limit the clinical impact and cost-effectiveness of this technique despite its lower cost.