Tumor necrosis factor alfa (TNF-α) is a cytokine with a central role in inflammation. Its blockade can be achieved by using specific inhibitors like etanercept. At present, etanercept is approved for rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, juvenile idiopathic arthritis and psoriasis treatment. However, it has been used with promising results in other inflammatory dermatoses. A case is presented of a 54-year-old man diagnosed with pyoderma gangrenosum. He completed treatment with oral prednisolone with favorable outcome, but with recurrence after glucocorticoid therapy withdrawal. Thalidomide was introduced, but after complaints of glove and sock paresthesia and hypoesthesia, the drug was discontinued. Taking into account the favorable outcome with thalidomide and the necessity of drug withdrawal, it was decided to introduce therapy acting on the same step in the inflammation cascade. In this regard, etanercept was initiated. The aim of this article is to present an alternative therapy for refractory pyoderma gangrenosum, along with a literature review.