Aim: To estimate the prevalence of viral marker negative HCC and to compare the clinical, biochemical, histological, radiological characteristics and initial treatment response among patients with viral marker negative and viral marker positive HCC. Methods: Medical records of patients diagnosed to have HCC visiting Aga Khan University Hospital, Karachi during January 1998 to December 2007 were reviewed. Patients were divided in to NBNC-HCC(those who have negative HBsAg and Anti-HCV antibody)and viral HCC(those who have positive HbsAg and Anti-HCV antibody)group. Results: Out of 433 patients 68(15.7%) had NBNC-HCC. Over all mean age was 57.48± 10.9 years and 69.5% were males. The proportion of HCC detected under surveillance was significantly smaller in NBNC-HCC group(p0.02). There was no difference in distribution of age, gender, BMI, child score, bilirubin, serum albumin, prothrombin time and Alfa Feto protein in both groups. However, patients with viral-HCC were found to be more thrombocytopenic(52.67±86.7vs.226.15±153.9,p<0.001) and had hepatopulmonary syndrome. On liver biopsy greater proportion of moderate to poorly differentiated HCC was observed in NBNC group(19.2%vs.7.9%,p<0.001). HCC measuring 5cm in diameter(60.3%vs.41.9%, p 0.01), non -solitary HCC(p0.038) and portal thromboses(p0.01) were strongly demonstrated in NBNC-HCC group. Involvement of right hepatic lobe and extra hepatic tumor spread was greater in NBNC-HCC group but that difference was not statistically significant. Out of 178 patients who underwent for liver transplantation(0.5%),TACE(36.7%),Resection(1%),ethanol ablation(2%) and chemotherapy(2%), poorer responses were observed in NBNC-HCC group (p 0.04). Conclusion: HCC secondary to NBNC-cirrhosis is not uncommon. Patients with NBNC-HCC tended not to be under surveillance that leads to diagnoses at more advanced stage and poor prognosis. 