F-fluciclovine is a PET radiotracer approved for detection of recurrent prostate cancer, with utility in other malignancies being investigated. We present the case of a 71-year-old man with high-risk primary prostate cancer (Gleason score 9, prostate-specific antigen 34 ng/mL) and newly diagnosed lung adenocarcinoma. As part of a clinical trial (NCT03081884), preoperative F-fluciclovine PET/CT showed localized abnormal uptake in the prostate gland with extracapsular extension. Additionally, an incidental anterior mediastinal mass measuring 2.2 × 1.8 cm demonstrated abnormal radiotracer uptake. Biopsy of the mediastinal mass confirmed invasive lung adenocarcinoma with solid and acinar patterns and high programmed death 1 ligand expression.