Background. MiR-122 is a liver-specific microRNA. The aim of the study was to explore the association of serum miR-122 with response to sorafenib in hepatitis B virus- (HBV-) related hepatocellular carcinoma (HCC) patients and to further reveal the effect of the virus load on such potential relationship. Methods. A total of 588 patients with HCC were retrospectively included. All of them were diagnosed with HBV-related locally advanced HCC and were treated with sorafenib. Therapeutic and prognostic information and other information were collected from medical records. Stored blood specimens that were obtained before sorafenib treatment were adopted to detect miR-122. Results. The patients were divided into high-level group and low-level group according to the median of serum miR-122 level, and each group contained 294 patients. During the first 24 weeks after sorafenib treatment, the patients in the high-level group had more opportunities to experience progression-free survival (PFS) and overall survival (OS) than those in the low-level group (HR: 2.47, 95%CI: 1.24∼4.88; HR: 1.20, 95%CI: 1.09∼1.32). In the subgroup analysis, the relationship between serum miR-122 level and overall survival still existed in the patients with relatively lower HBV load (HR: 1.22, 95%CI: 1.09∼1.36), but not in the patients with higher HBV load (HR: 1.12, 95%CI: 0.93∼1.35). Conclusion. Higher serum level of miR-122 at baseline was associated with a better response to sorafenib in HBV-related locally advanced HCC patients, and relatively high HBV load weakened such predictive effect mentioned above.