Background: In two previous phase 3 studies, up to 60 weeks of etanercept therapy significantly improved the symptoms of psoriasis and was well tolerated. Objective: To evaluate the long-term safety of etanercept in an open-label extension study for up to 72 weeks in patients with moderate-to-severe plaque psoriasis. Methods: A total of 912 patients received 50 mg subcutaneous etanercept once weekly (QW) for the first 12 weeks of this extension study. Thereafter, eligible patients could maintain the 50 mg QW dose (n=321) or escalate to 50 mg twice weekly (BIW; n=591) anytime thereafter based on one of three predetermined criteria. Results: Etanercept was well tolerated during 1056 patient-years of exposure; no difference was observed between the 50 mg QW and 50 mg BIW dosages in rates of adverse events and infections. Improvement in skin disease was maintained throughout the study. Patients who stopped and then restarted etanercept also showed improvement in psoriasis. Conclusion: Psoriatic patients continued to benefit from open-label etanercept treatment, both continuous and interrupted therapy, which was generally well tolerated after a combined 2.5 years of experience. Copyright © 2010 Journal of Drugs in Dermatology.