Liver adenomatosis is defined by the presence of multiple hepatic adenomas (more than three lesions). The natural history and treatment of liver adenomatosis are not yet well defined. The Mayo Clinic (Rochester, MN) experience with liver adenomatosis in the past 11 years was reviewed and a rational treatment approach is presented. Records from patients with liver adenomatosis and hepatic adenoma seen at the Mayo Clinic from January 1986 to June 1997 were reviewed. Estrogen- and progesterone-receptor status was assessed by immunohistochemistry. Eight women with liver adenomatosis were identified. All patients had undergone surgical treatment. Abdominal pain was the presenting symptom in 87.5% of the patients with adenomatosis and in 42.1% of the patients with hepatic adenoma. Tumor bleeding was present in 62.5% of the patients with adenomatosis and in 26.3% of the patients with hepatic adenomas. Bleeding occurred predominantly in lesions greater than 4 cm. All patients with liver adenomatosis reported improvement of symptoms after surgery, and the mean bleeding-free period after resection in 5 patients was 52.6 +/- 23.6 months. In 6 patients, estrogen receptor-positive and estrogen receptor-negative tumors were identified in the same liver. Based on the good outcome after resection in symptomatic patients with liver adenomatosis, we recommend resection of large (>/=5 cm) or symptomatic lesions with observation of smaller lesions (</=3 cm). Lack of estrogen receptors in many lesions suggests that estrogen does not play a dominant role in the pathogenesis of liver adenomatosis.