The diagnostic work-up in patients with fever of unknown origin (FUO) is often challenging and frequently includes nuclear medicine procedures. Whereas a role for leucocyte or granulocyte scintigraphy in FUO is generally accepted, a possible role of fluorine-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) in these patients remains to be established. To study this, we compared prospectively, on a head-to-head basis, the diagnostic value of FDG-PET and indium-111 granulocyte scintigraphy in patients with FUO. Nineteen patients with FUO underwent both FDG-PET and (111)In-granulocyte scintigraphy within 1 week. FDG-PET scans and granulocyte scintigrams were reviewed by different doctors who were blinded to the result of the other investigation. The diagnostic values of FDG-PET and granulocyte scintigraphy were evaluated with regard to identification of a focal infectious/inflammatory or malignant cause of FUO. The sensitivity of granulocyte scintigraphy and FDG-PET were 71% [95% confidence interval (CI): 37-85%] and 50% (CI: 16-84%), respectively. The specificity of granulocyte scintigraphy was 92% (71-100%), which was significantly higher than that of FDG-PET, at 46% (34-62%). Positive and negative predictive values for granulocyte scintigraphy were both 85%. Positive and negative predictive values for FDG-PET were 30% and 67%, respectively. (111)In-granulocyte scintigraphy has a superior diagnostic performance compared to FDG-PET for detection of a localised infectious/inflammatory or neoplastic cause of FUO. The poorer performance of FDG-PET is in particular attributable to a high percentage of false positive scans, leading to low specificity.