Primary hepatocellular carcinoma (HCC) is the fifth most frequently reported malignancy, and it is also the second most common cause of cancer-related deaths worldwide. Although most HCC cases have been reported to develop from cirrhosis, accumulating data suggest that HCC is also closely related to non-cirrhotic chronic liver disease. Traditionally, HCC was thought to develop mostly from cirrhosis; however, an increasing number of reports have found that HCC can develop directly from inflammation without cirrhosis. The incidence of HCC in non-cirrhotic liver (HCC-NCL) is high, especially in developed countries. Studies have found that the most common cause of HCC-NCL is neglected fatty liver disease. This type of HCC has unique clinical characteristics and is closely related to metabolic disorders. Unfortunately, the prevention of HCC-NCL has not received enough attention worldwide, and there is also a lack of specific screening methods and clinical guidelines. This article mainly reviews the etiology, incidence, clinical characteristics, and screening markers of HCC-NCL to improve the understanding and prevention of this disease.