Psoriasis rebound after efalizumab discontinuation is well-documented in the literature. We report the case of a patient who experienced psoriasis rebound 2 months after efalizumab discontinuation, despite being on more than 5 mg/kg/day of cyclosporine. This case illustrates an instance where high doses of a very efficacious antipsoriasis therapy were not sufficient to prevent efalizumab-associated rebound. In addition to describing this case, we also propose a theoretical mechanism to explain how rebound after efalizumab discontinuation comes about.