Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related mortality worldwide and remains one of the few malignancies with steadily increasing incidence and death rates over recent years. Globally, major etiological drivers of HCC include chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections, consumption of aflatoxin-contaminated food, heavy alcohol intake, obesity, cigarette smoking, and type 2 diabetes mellitus. In China, however, the exceptionally high burden of HCC is primarily attributable to chronic HBV infection and aflatoxin exposure, with approximately 80% of Chinese HCC patients testing positive for HBV. The natural history of the disease generally progresses from chronic hepatitis to liver cirrhosis and ultimately to HCC. Throughout this trajectory, the infection-associated microecological environment exerts a crucial influence on hepatocarcinogenesis. This chapter will examine the role and mechanistic underpinnings of infection-related microecology—particularly the gut microbiome—in the development of HCC and highlight the clinical relevance of infection-associated microbial components in liver cancer treatment.