The metabolic syndrome may cause disease progression in patients with chronic hepatitis B (CHB). However, the interactions between hepatitis B virus (HBV) infection and metabolic factors remain unknown. We investigated the association of HBV infection with metabolic profiles in HBV-infected and noninfected subjects. In addition, the impacts of serum HBV DNA level on metabolic profiles were studied. Initially, a case-control analysis of patients with and without chronic HBV infection was performed. The HBV group consisted of 322 patients with chronic HBV infection, and the control group consisted of 870 matched subjects without HBV infection. Fasting blood glucose, lipid profiles and adiponectin levels were compared. The results were then confirmed in a second retrospective cohort study in 122 CHB patients with serum HBV DNA levels and HOMA-IR index values. In the case-control analysis, the HBV group had significantly higher serum adiponectin, but lower triglyceride (TG) and high-density lipoprotein cholesterol (HDL) levels than the control group. These relationships already existed in subjects younger than 45 years of age and were modified by serum alanine aminotransferase (ALT) levels. In the retrospective cohort, serum HBV DNA levels were negatively proportional to TG levels, but not to other metabolic parameters. Moreover, this relationship was significant only in subjects with higher ALT levels. Compared with healthy adults, patients with chronic HBV infection have significantly higher serum adiponectin, but lower TG and HDL levels. These relationships are modified by ALT levels and already exist in middle-age patients with chronic HBV infection, implying HBV may interact with host metabolism.