A 74-year-old man presented with rapid rising prostate-specific antigen (PSA) 2 years after treatment of prostate cancer with prostatectomy and salvage radiation therapy. PSA increased from 923 to 4349 ng/mL within 2 months. No osseous metastatic lesions of prostate cancer were detected by 18F-sodium fluoride PET/CT imaging at an outside facility. 18F-fluciclovine PET/CT imaging was performed to evaluate local recurrence of prostate cancer at surgical bed of prostatectomy and distant metastasis. One small focus of low-level 18F-fluciclovine radiotracer uptake was noted in the surgical bed of prostatectomy without corresponding soft tissue mass on CT. No fluciclovine-avid lymph nodes or osseous metastatic lesions were detected, but multiple hypodense lesions of variable 18F-fluciclovine radiotracer uptake were noted in the liver, concerning for isolated liver metastasis of prostate cancer. The patient underwent docetaxel chemotherapy for treatment of prostate cancer liver metastasis and showed a favorable response to treatment by significant decreased size of the hypodense lesions in the liver on post treatment abdominal CT, along with dramatic reduction of PSA level and improvement of liver function. The findings from this case highlight the importance of checking hypoattenuating lesions in the liver for the presence of prostate cancer metastatic lesions that might appear similar to other benign hypoattenuating lesions of low fluciclovine uptake relative to physiological 18F-fluciclovine uptake in the normal liver tissues, a potential pitfall at interpretation of 18F-fluociclovine PET/CT imaging.