In a randomized controlled trial, 165 healthy medical students were immunized either by the intramuscular route (IM group) or by the intradermal route (ID group) with low-dose (2 μg) plasma hepatitis B vaccine (HB-VAX) at months 0, 1, 2, and 6. At month 7, protective immunity (anti-HBs > 10 IU/I) was observed in 90% (95% confidence interval [CI]: 84–97) of group IM and in 94% (95% CI: 89–99) of group ID; also geometric mean titres (IM: 533 IU/I ID:541 IU/I) were very similar at month 7. Sixty-six (IM: 29; ID: 37) of 107 vaccinees with anti-HBs < 1,000 IU/I at month 7 received a 2 μg booster injection at month 12. Long-term immunity (anti-HBs > 1,000 IU/I) was finally observed in 58% for group IM and 66% for group ID. For low-dose hepatitis B immunization, which reduces costs to about 16%, the IM route is to be preferred in young healthy individuals in view of an ease of administration, avoidance of long-term local side effects, and the known protective immunity of intramuscularly induced anti-HBs antibodies.