The medical records of women taking part in the first 2 prospective adjuvant CMF (cyclophosphamide, methotrexate, fluorouracil) programs were reviewed to evaluate the incidence of liver damage which could be attributable to prolonged methotrexate administration. In 802 evaluable patients abnormal liver studies occurred in 7 of 170 controls (4.1%) and 20 of 632 CMF-treated patients (3.2%). In 22 of 27 patients they were reversible, while the persistence of enzyme abnormalities in 2 patients treated with 12 CMF cycles was followed by the occurrence of viral hepatitis and osseous metastases, respectively. Adjuvant CMF was never discontinued in the presence of liver function abnormalities. In 22 women liver biopsies through laparoscopy were performed for various diagnostic purposes. They yielded an incidence of aspecific histologic changes (fatty metamorphosis, subcapsular fibrosis) which was similar between controls and CMF-treated patients. Present analysis failed to demonstrate a higher incidence of acute and/or chronic liver changes in patients treated with cyclical CMF compared to controls treated with surgery alone.