Beta-interferon therapy is known to trigger psoriasis, but this effect has not been previously reported for other multiple sclerosis treatments, such as natalizumab. The following is a case report. A 31-year-old woman affected by psoriasis and relapsing-remitting multiple sclerosis suffered a severe worsening of psoriasis symptoms during natalizumab treatment and acquired a drug-resistant course. This case suggests that aggravation of psoriasis might be a rare side effect of natalizumab, and that clinicians should be aware of the possibility of paradoxical activation of autoimmune diseases during its treatment.