Megaprosthesis is used to restore the form and function of massive skeletal defects, but it is accompanied by risks of failure, mainly due to perimegaprosthetic infection (PMI). In practice, the diagnosis of infected megaprosthesis among patients with a high index of clinical suspicion, elevated serological markers, and multiple negative or inconclusive imaging can be very challenging and poses a diagnostic conundrum to many orthopaedic surgeons. We present the case of a symptomatic 26-year-old female with large B-cell lymphoma who developed cellulitis with suspected complication of PMI 15 months post-implantation. The combination of advanced nuclear medicine imaging strategies, i.e., 99mTc-besilesomab/ 99mTc-sulfur colloid scintigraphy with hybrid single-photon emission computed tomography/computed tomography (SPECT/CT) scanning helps to characterise and delineate both infections. Invasive procedures such as joint aspiration and biopsy were avoided, and the patient was successfully treated with antibiotics. Hence, we report a case where advanced imaging modalities were decisive in the investigation of PMI.