Background Hepatocellular carcinoma represents 85%—90% of primary liver tumors; it represents the 2nd leading cause of cancer-related death all over the world. There is a growing incidence of HCC worldwide and similarly, the incidence of HCC has almost doubled over the last decade in Egypt. Aim of the work To assess clinico-epidemiological character of HCC in the last two decades and to compare between the first and second decade regarding these characters. Patients and methods This retrospective study included 497 HCC patients’ data collected from Clinical Oncology and Nuclear Medicine Department from 1999 to 2019, HCC patients were classified into 1st decade (from 1999 to 2009) and 2nd decade (2010 – 2019). Diagnosis of HCC was based on clinical, laboratory, (AFP), and radiological examinations (The abdominal US and triphasic CT scan). Results The study revealed that the average age of HCC cases was 57 years, the majority of these were males (88%), residents in rural areas (70%), about one-fourth of them, were smokers (26.4%), DM was present in 14% of these while only 7% were hypertension. Thirty presents (30%) of them were represented by ascites and (20%) by hepatic encephalopathy of different grades. The majority of HCC patients (92.2%) have HCV Abs positive. HBS Ag was positive in 2.4% while mixed infection (HCV Abs + ve and HBS Ag + ve) was in 2% of patients only. The median level of AFP was 300 ng/ml. The severity of underlying chronic liver disease was assessed by the Child–Pugh score the mean score was 7.5 (from 6–11) and the MELD score (the mean score was 18.8 (from 6–29). Regarding tumor characteristics, HCC mass was located in the Right lobe of the liver in (63.8%), in the left lobe in (26.6%) and both lobes were affected in 9.6%. A single focal hepatic lesion was detected in about 60% of patients, 3 focal lesions in about 20%, and two focal lesions or multifocal HCC in the remaining percent. The median size of the largest tumor’s diameter was 5 cm by the US and 5.3 cm by the triphasic CT. PVT, vascular invasion, LN, and distant metastasis were detected in (35.6%), (40%), (40%) and (54%) of patients respectively. In less than one-third of HCC cases, the tumors were within Milan criteria (30%). Conclusion The 1st decade showed a significantly higher frequency of patients presented with marked splenomegaly and splenectomy, while the second decade showed a significantly higher frequency in patients who reside in rural areas. Higher frequency of DM, advanced hepatic encephalopathy grade III/ IV, and unfortunately more aggressive tumors with PVT, vascular invasion, LN metastasis, and distant metastasis were detected in the 2nd decade.