Diffuse liver infiltration by melanoma of unknown primary origin is rare. We encountered a unique case of diffuse liver infiltration by melanoma of unknown primary origin in our hospital. A 62-year-old woman was referred to our hospital for anorexia of 6 months duration and abdominal distension for 1 month. Ultrasonography (US), computerized tomography (CT) and magnetic resonance imaging (MRI) revealed an obvious enlarged liver without detectable nodules. She was diagnosed as liver metastasis by melanoma of unknown primary origin via percutaneous liver biopsy. The report demonstrates the difficulty of making a noninvasive diagnosis of diffuse hepatic infiltration on metastatic melanoma.