Hepatitis B viral (HBV) infection is one of the major causes of Hepatocellular Carcinoma (HCC). Previous studies had provided evidence that HBV integration may be an important factor for HCC carcinogenesis. In order to establish a new strategy for HCC diagnosis, a novel method was deployed to screen for HBV integration sites in both the HCC tumor and the paired plasma samples. HBV (type B) infections were detected in both patients, and a total number of 24 HBV viral integration sites were documented. Interestingly, one of the integration sites, in particular, was detected in both the HCC tumor and the paired plasma samples. In addition, it was noticed that HBV breakpoints inclined to the region of X protein (1,700-2,000 bp) in both the HCC tumor and the paired plasma samples. Altogether, our results provided evidence for HBV integration in plasma DNA, and they might be potentially useful for future HCC prognosis and diagnosis.