Objective To investigate the efficacy and safety outcomes of combination therapy used to optimize etanercept treatment in patients with psoriasis treated in real-life clinical practice. Methods Data from patients presenting with psoriasis, treated initially with etanercept monotherapy, were analysed retrospectively. Patients subsequently treated with combination therapy were further analysed. The Psoriasis Area and Severity Index (PASI) score was recorded for all patients receiving comedication; a subjective pain score was recorded in those with psoriatic arthritis receiving comedication after 12, 24 and 48weeks' treatment and thereafter at 6-month intervals. Results From the database of 400 patients treated with etanercept, 37 patients (18 male; 19 female; mean age 59.43years) underwent combination therapy due to lack of efficacy. Patients received mostly short-term (range 4-34weeks) comedication with corticosteroids, cyclosporine, methotrexate, nonsteroidal anti-inflammatory drugs, acitretin or sulphasalazine. There were significant reductions in the mean PASI score from baseline at all timepoints. There were also significant reductions in the mean pain VAS score from baseline at all timepoints in patients with psoriatic arthritis. The drug survival rate was 59.6% over a mean duration of 323weeks of etanercept treatment. The safety profile of combination therapy was satisfactory. Conclusions Short-term comedication in combination with etanercept may optimize treatment options and improve long-term drug survival in patients with psoriasis.