Pyoderma gangrenosum is an unusual inflammatory pathology, with neutrophilic dermatosis, of unknown etiology. It is associated with diseases such as bowel disease. Generally, it is treated with anti-inflammatory drugs, corticosteroids, immunosuppressants, and antibodies against tumor necrosis factor, but relapse and adverse effects are persistent. Pentoxifylline is a drug with immunoregulatory and anti-inflammatory properties. A 47-year-old male with a diagnosis of ulcerative colitis initially managed favorably for 7 years with mesalazine. At 3 years of treatment, he presented a sudden ulcer that affected skin and subcutaneous tissue (13×10 cm) in the lower right limb. During the last 2 years, he was treated with mesalazine and infliximab with partial results and permanent relapses. Therefore, pentoxifylline was added to his treatment. The justification for the addition of pentoxifylline is mainly its action as an inhibitor of Nuclear Factor-kappa Beta (NF-κB) transcription, which stimulates the expression of proinflammatory interleukin genes such as IL-1, IL-6, IL- 8, and TNF-α and showing immunoregulatory and antioxidant activities. With pentoxifylline, this lesion healed at 6 weeks without relapses after 2 years.