Life-long hepatitis B immunoglobulin (HBIG) administration is a main component of prophylactic strategy to prevent hepatitis B virus (HBV) reinfection after liver transplantation (LT). Long-term effects of HBIG treatment are known only for intravenous (IV) and intramuscular formulations. To evaluate safety and efficacy of self-administered SC HBIG, 135 LT patients receiving a 48-week treatment were analyzed. The dose of HBIG was 500 IU or 1000 IU if body weight was <75 kg or ≥75 kg, respectively. Patients were switched from the monthly IV HBIG treatment to weekly SC HBIG 2–3 weeks after the last IV dosage. All patients were able to SC self-injection after a single training. The treatment was effective in maintaining trough anti-HBs levels >100 IU/L. No severe drug-related side effects occurred. Fifteen injection-site small hematomas and four cases of mild itch occurred. At the end of the study, anti-HBs median titer was 232 IU/L (115–566 IU/L) and 97.8% of patients had an anti-HBs level >150 IU/L. Due to high mean level of anti-HBs titers observed during this study, individualized treatment schedules should be further investigated. In conclusion, SC HBIG for long-term prophylaxis of post-LT HBV reinfection resulted safe, well accepted, and effective in maintaining adequate anti-HBs levels.