Background Periprosthetic joint infection (PJI) with sepsis is a life-threatening condition and identification of synchronous foci of infection is challenging. Positron emission tomography using 18F-fluorodeoxyglucose combined with computed tomography (18F-FDG-PET/CT) is useful to detect PJI in elective, nonseptic patients. We hypothesized that in patients who have PJI and concomitant sepsis requiring intensive care, 18F-FDG-PET/CT could accurately identify synchronous foci of infection. We addressed the following questions: (1) How often were synchronous foci of infection detected?; (2) What were the confirmation rates of these infection foci by other complementary state-of-the-art methods?; (3) Did 18F-FDG-PET/CT findings result in surgical treatment?; and (4) What is the risk of synchronous PJI in patients who have PJI and concomitant sepsis who have another indwelling arthroplasty? Methods We retrospectively analyzed mechanically ventilated septic PJI patients who underwent 18F-FDG-PET/CT between January 1, 2017 and December 21, 2022. The identified synchronous foci of infection were categorized into musculoskeletal, cardiovascular, pulmonary, or other infections and compared to results from tissue culture, histopathology, magnetic resonance imaging, or transesophageal echocardiography. Results We identified 17 eligible patients. The 18F-FDG-PET/CT revealed at least one additional infection focus in 15 patients with the following distribution: musculoskeletal (n = 12), cardiovascular (n = 3), pulmonary (n = 13), and other infections (n = 6). Synchronous foci of infection identified with 18F-FDG-PET/CT were confirmed by another state-of-the-art method in 1 all 15 patients. Diagnoses with 18F-FDG-PET/CT led to additional surgery in 11 patients. Of the patients, 10 of 17 had another arthroplasty with a risk in three of synchronous PJI. Conclusions We highlight the value of 18F-FDG-PET/CT in patients who have PJI and sepsis, emphasizing its role in the comprehensive evaluation of these patients for subsequent therapeutic decision-making.