Interleukin-2 (IL-2) therapy is associated with serious toxic effects on the cardiopulmonary system. Less frequent toxicity is described in liver and the gastrointestinal system. A case of severe liver toxicity is described in a patient who underwent long-term immunotherapy with IL-2 (4.5 MU/m(2) s.c. daily, 5 days per week for 6 weeks, with 4 weeks of interval) plus interferon-alpha (IFN-alpha) (3 MU s.c. t.i.w., also covering the intervals between IL-2 cycles) for a metastatic renal carcinoma. A review of the literature is provided. The patient tolerated well the immunotherapy scheduled with apparently only a World Health Organization (WHO) G3 anemia and a G2 asthenia and is still alive, with a disease-free survival of 28 months. Notwithstanding a complete absence of liver function test abnormality during all scheduled clinical controls, the patient developed portal hypertension due to liver cirrhosis, which was histologically demonstrated. All common etiologic viral and toxic agents were ruled out. Long-term IL-2 therapy can induce liver cirrhosis. The appearance of liver and spleen enlargement during IL-2 therapy can be considered an indicator of liver damage. Thus, in this setting, closer monitoring is warranted despite normal liver function tests.