Hepatitis B immunoglobulin (HBIG) administration remains an essential component of standard reinfection prophylaxis after liver transplantation for hepatitis B virus–related liver disease. Previous studies have suggested that intramuscular (IM) HBIG administration compared to intravenous (IV) HBIG administration may be cost-effective and dose-saving. To compare antibody against hepatitis B surface antigen (anti-HBs) kinetics after IV HBIG administration versus IM HBIG administration, 24 patients received 2000 IU of HBIG every 6 weeks over a study period of 48 weeks in a crossover design. HBIG was started intravenously in 12 patients (group A) and intramuscularly in 12 patients (group B). After 4 doses, at week 24 HBIG administration was switched from IM to IV and vice versa. Anti-HBs kinetics of 22 patients were evaluated. Mean anti-HBs levels measured 2, 4, and 6 weeks after each HBIG administration did not differ significantly (480 ± 166, 319 ± 126, and 221 ± 106 IU/L after IV administration versus 457 ± 166, 310 ± 147, and 218 ± 112 IU/L after IM administration). Half-lives of anti-HBs decline (IV, 25.5 ± 6.0 days, versus IM, 24.7 ± 6.2 days) and area under the curve values from week 2 to 6 (IV, 9.4 ± 3.6 IU*day/mL, versus IM, 9.0 ± 3.9 IU*day/mL) also showed no significant difference. Variation of anti-HBs levels after IV HBIG administration versus IM HBIG administration was neither significantly different within patients (intraindividual variance) nor between patients (interindividual variance). However, intraindividual variance was lower than interindividual variance after IV (P < 0.05) and IM (P < 0.05) HBIG administration at every time point (2, 4, and 6 weeks). In conclusion, IV HBIG administration and IM HBIG administration are equally effective with respect to the crucial pharmacokinetic parameters. That is, IM HBIG is not dose-saving; however, it may be cost-effective if the price per unit is lower. Individualized dosing intervals should be further evaluated as a cost-effective alternative to fixed dosing schemes. Liver Transpl 14:435–442, 2008. © 2008 AASLD.