We aimed to compare the accuracy of fluorodeoxyglucose positron emission tomography (FDG-PET) with technetium-99m sulfur colloid (111)indium-labeled white blood cell scintigraphy (TcSC-Ind BM/WBC) in diagnosis of periprosthetic infection. Eighty-nine patients with 92 painful hip prostheses were recruited prospectively and given the option of undergoing either combined FDG-PET and TcSC-Ind BM/WBC or FDG-PET only. FDG-PET correctly diagnosed 20 of the 21 infected cases (sensitivity, 95.2%) and ruled out infection in 66 of the 71 aseptic hips (specificity, 93%) corresponding to a positive predictive value of 80% (20/25) and a negative predictive value of 98.5% (66/67). TcSC-Ind BM/WBC correctly identified 5 of the 10 infected cases (sensitivity, 50%) and 39 of 41 aseptic cases (specificity, 95.1%) corresponding to a positive and negative predictive values of 41.7% (5/12 cases) and 88.6% (39/44 cases), respectively. Based on these preliminary results, FDG-PET appears to be a promising diagnostic tool for distinguishing septic from aseptic painful hip prostheses.