A major aim of current research in breast cancer is more effective targeting of chemotherapy. Biological markers may provide one way of identifying patients more or less likely to respond to a particular therapy/regimen. HER-2 overexpression appears to be a potential indicator of responsiveness to doxorubicin and paclitaxel, and conversely of unresponsiveness to tamoxifen. It has been suggested that HER-2 overexpression may result in a decrease in responsiveness to cyclophosphamide, methotrexate, and fluorouracil (CMF). This study examined HER-2 overexpression and clinical benefit in the 386 node-positive breast cancer patients in the first trial of CMF versus no treatment with a 20-year follow-up.