Infection of rabbits with aerosolized rabbitpox virus (RPXV) produces a disease similar to monkeypox and smallpox in humans and provides a valuable, informative model system to test medical countermeasures against orthopoxviruses. Due to the eradication of smallpox, the evaluation of the efficacy of new-generation smallpox vaccines depends on relevant well-developed animal studies for vaccine licensure. In this study, we tested the efficacy of IMVAMUNE ® [modified vaccinia Ankara-Bavarian Nordic (MVA-BN ®)] for protecting rabbits against aerosolized RPXV. Rabbits were vaccinated with either phosphate-buffered saline (PBS), Dryvax ®, a single low dose of IMVAMUNE ®, a single high dose of IMVAMUNE ®, or twice with a high dose of IMVAMUNE ®. Aerosol challenge with a lethal dose of RPXV was performed 4 weeks after the last vaccination. All PBS control animals succumbed to the disease or were euthanized because of the disease within 7 days postexposure. The rabbits vaccinated with Dryvax ®, a low dose of IMVAMUNE ®, or a single high dose of IMVAMUNE ® showed minimal to moderate clinical signs of the disease, but all survived the challenge. The only clinical sign displayed by rabbits that had been vaccinated twice with a high dose of IMVAMUNE ® was mild transient anorexia in just two out of eight rabbits. This study shows that IMVAMUNE ® can be a very effective vaccine against aerosolized RPXV.