Mucosal leishmaniasis is characterized by an intense inflammatory reaction and tissue damage with few parasites in the lesion. On the basis of previous observations that suggest a possible role of tumor necrosis factor alpha (TNF-alpha) in the pathology of this disease, an open-label study was performed to evaluate the efficacy of the treatment with an inhibitor of TNF-alpha (pentoxifylline) associated to antimony therapy in 10 patients with refractory mucosal leishmaniasis. Patients were treated with pentavalent antimony (20 mg per kilogram of body weight per day) plus orally administered pentoxifylline 400 mg 3 times daily for 30 days. Nine of 10 patients fulfilled the criteria for cure: they experienced complete reepithelization of the mucosal tissue 90 days after therapy and displayed no evidence of relapse at 1 year of follow-up. The TNF-alpha levels before therapy (776 +/- 342 pg/mL) fell to 94 +/- 57 pg/mL (P < 0.05) within 60 days after therapy. Our results indicate that pentoxifylline plus antimony therapy should be considered in all patients with mucosal leishmaniasis that is refractory to treatment.