The PHOEBE study showed that pyrotinib is an alternative treatment option for patients with human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer after trastuzumab and chemotherapy. Diarrhea was a common adverse event that could compromise or modify treatment administration.We conducted a retrospective cohort study of HER2-positive advanced breast cancer patients receiving a pyrotinib-based regimen between August 2018 and January 2021. The risk of diarrhea with 95% confidence limits (CLs) was calculated and management was analyzed.A total of 46 HER2-positive advanced breast cancer patients were enrolled. Diarrhea of any grade occurred in 100% of patients, and grade 3 diarrhea was observed in 52.2% (n=24) of patients. Treatment dose modification was implemented in 39.1% (n=18) of advanced breast cancer patients. Compared with other treatment regimens, patients receiving pyrotinib plus vinorelbine suffered the highest risk of diarrhea (60%), though no significant difference was confirmed (P=0.77). Antidiarrheal agents were commonly used and loperamide-based regimens achieved an ideal antidiarrheal effect (95.3-100%), while non-loperamide-based regimens (such as montmorillonite powder) had a lower control rate (78.6%).Diarrhea was a common adverse event of pyrotinib-based treatment, and approximately 50% of patients suffered high grade diarrhea. Loperamide-based antidiarrheal agents could commendably manage most episodes.