Despite many millions of doses administered over the past 40 years, basic and crucial issues regarding the use, mode of action, and effectiveness of diethylcarbamazine (DEC) in many clinical situations remain unresolved. To directly investigate whether the well-known microfilaricidal and macrofilaricidal actions of DEC actually result in subsequent improvement in existing damage to lymphatic vessels or lymph nodes, 29 study subjects in Recife, Brazil were stratified into three groups according to the severity of clinical manifestations of lymphatic insufficiency. After baseline radionuclide lymphoscintigraphy was performed, subjects were treated with two courses of DEC separated by at least a six-month interval and then rescanned one year after the baseline scan. A side-by-side comparison of images obtained at baseline with those obtained at follow-up in 13 asymptomatic microfilaremic individuals, six individuals with filarial fever, and in 10 individuals with chronic pathology demonstrated essentially unchanged lymphatic morphology in all but one individual whose disease actually progressed in the face of therapy. We conclude that two 12-day treatment courses of DEC did not have a demonstrable direct or indirect effect on existing structural damage to the lymphatic system even in those individuals with preclinical disease.