Neratinib is an oral, irreversible, pan-tyrosine kinase inhibitor (TKI) of human epidermal growth factor receptor 1 (HER1), HER2, and HER4, which usually been used in combination with capecitabine for advanced HER2 positive breast cancer. Here we report an interesting case of a HER2 positive advanced breast cancer patient who received neratinib monotherapy with 240 mg daily for more than 14 years after several lines of chemotherapy combined with trastuzumab and the target lesions in the liver nearly disappeared. As far as we know, this is the case with the longest benefit from neratinib monotherapy. A 56-year-old female was diagnosed HER2 positive breast cancer in 2004 and developed liver and bone metastases in 2006. Then she received several lines of chemotherapy including capecitabine, gemcitabine, and docetaxel combined with trastuzumab and the best curative effect was stable disease (SD). Then she was enrolled in a new drug (neratinib) clinical trial and treated with neratinib alone. The lesions in the liver were diminishing quickly and no longer growing up for more than 14 years. Due to the end of the clinical trial, the patient had to change drug to pyrotinib which had a similar mechanism with neratinib from August 2021. Patients may benefit from switching to another anti-HER2 drugs with different mechanism of action after the failure of prior anti-HER2 therapy.