Etanercept is a dimeric fusion protein based on the p75 TNF-alpha receptor. It binds to TNF-alpha and blocks its biologic activity. In randomized, double-blind, placebo-controlled trials, etanercept has therapeutic activity in rheumatoid arthritis, psoriatic arthritis, polyarticular-course juvenile idiopathic arthritis and ankylosing spondylitis. Etanercept improves joint inflammation, physical function and slows/halts structural damage, especially when combined with methotrexate. A sustained response is observed in a substantial percentage of patients. Although some safety issues should be considered before starting etanercept treatment, in general terms, etanercept is a well tolerated drug with an acceptable safety profile. The use of any TNF-alpha antagonist must be in agreement with the National Recommendations for Biologic Therapy, and in difficult clinical situations, a balance between risk/benefit needs to be obtained.