Since targeted biologic treatments have been introduced for the treatment of plaque-type psoriasis and psoriatic arthritis, switching between different medications has become necessary in selected patients, particularly after treatment failures. To evaluate the efficacy and safety of etanercept treatment in adult patients with psoriasis after failure to respond to other previous therapies. In particular, the differences in efficacy profiles after switching from traditional (cyclosporine [ciclosporin], methotrexate, retinoids, fumaric acid esters, psoralen plus UVA therapy, corticosteroids) or biologic (infliximab, efalizumab) treatments were analyzed. The study included 124 patients affected by plaque-type psoriasis who received etanercept administered subcutaneously at a dosage of 50 mg twice weekly for 12 weeks, followed by 25 mg twice weekly for an additional 12 weeks, and 110 patients affected by psoriatic arthritis who were treated with etanercept 25 mg twice weekly in a continuous regimen, after a 12-week period of treatment with etanercept 50 mg twice weekly. Efficacy results were consistent in both groups of patients (plaque-type psoriasis and psoriatic arthritis), as expressed by the percentage of patients who achieved Psoriasis Area and Severity Index (PASI) 50 and PASI 75 scores. Among psoriatic arthritis patients, the mean pain Visual Analog Scale (VAS) score showed a substantial reduction during the treatment course, from 67.2 at week 0 to 15.8 at week 24. After 24 weeks, among patients with plaque-type psoriasis who had not previously received biologic therapies, 89.9% of patients achieved PASI 50 and 75.3% achieved PASI 75, while among patients who had received biologic therapies, 69.6% of patients achieved PASI 50 and 65.2% achieved PASI 75. In addition, 92.3% of patients with psoriatic arthritis who had not previously received biologic therapies achieved PASI 50 and 73.8% achieved PASI 75, while among patients who had received biologic therapies, 45.8% of patients achieved PASI 50 and 29.2% achieved PASI 75. Our study demonstrated that etanercept was more effective in those patients who had not previously received other biologic therapies than in those who had. The results of the present study indicate that etanercept may represent a valid, effective, and well tolerated therapeutic alternative even after failure to respond to traditional and other biologic therapies.