The incidence of hepatocellular carcinoma (HCC) appears to be increasing across the globe. Well-established protocols for screening are available, and the most common underlying liver problem associated with the development of HCC is cirrhosis. However, with few exceptions, patients without cirrhosis are generally not screened for HCC. Nodular regenerative hyperplasia (NRH) is not associated with the development of significant fibrosis or impaired liver synthetic function. The major clinical impact of NRH appears to be in the development of portal hypertension. Patients with NRH are also not recommended to undergo routine screening for the development of HCC. This report describes a case of a 44-year-old woman with NRH found to have de novo HCC. Emerging evidence suggest a possible pathogenetic relationship between NRH and HCC. The case described here and our review of the published work suggests that additional studies regarding the epidemiological association between NRH and HCC may change the current notion that NRH is not a premalignant lesion, and further studies assessing the utility of routine screening of NRH patients for HCC should be considered.