Background: Cancer immunotherapy became a promising alternative to old therapeutic options in hepatocellular carcinoma. DC-DRibbles vaccine has clinical applications across a broad range of malignancies. Objective: To compare the efficacy of subcutaneous and intranodal routes of injection of Dendritic Cells-DRibbles immunotherapy in HCC induced mice. Methodology: This experimental study was conducted on 24 BALB/c mice. Healthy as negative control and cancer induced. The later was subdivided into two groups: positive control group and vaccinated groups (A and B) according to route of administration. Results: The mean of percentage of tumor volume reduction was 92.76% in DC+ Dribbles intranodal group (B), which was better than mean of percentage of change in subcutaneous group (A) which was 90.87%. Conclusion: DC- Dribbles vaccine was effective as HCC immunotherapy, both subcutaneous and intra nodal routes had comparable results. This study recommends subcutaneous route over intranodal route immunotherapy; it is simple, less invasive and effective.