The aim of this pilot study was to investigate the effect of intravitreal administration of etanercept in refractory diabetic macular edema. Seven patients diagnosed with diabetic macular edema, refractory to previous treatment, were enrolled. They all received 2 consecutive intravitreal injections of 2.5 mg (0, 1 ml) of Etanercept (Enbrel), with a two-week interval. In all patients visual acuity assessment, fundoscopy and fluorescein angiography were performed prior to the first injection, weekly for the first month, as well as 2 and 3 months following the first injection. No adverse reactions or adverse events were noticed in any patient. Analysis of the data indicates a trend for improvement of visual acuity, a slight worsening of hard exudates and fluorescein leakage, while hemorrhages remained stable, 3 months after initiation of therapy. However, no statistical significance has been reached. This small pilot study did not reveal any improvement in the clinical course of patients with refractory diabetic macular edema after the intravitreal injection of etanercept. Further research is warranted in order to obtain conclusive results concerning the role of anti-TNF therapy in diabetic macular edema.