Background: Pyrotinib, an irreversible pan-HER tyrosine kinase inhibitor, has been a salvage regimen for metastatic HER2+ breast cancer failed to trastuzumab in Chinese guidelines. However, the incidence of pyrotinib induced diarrhea is more than 80% as neratinib. TCM-padia001 (clinicaltrials.gov: NCT04988165) is an open-label, phase II study investigating the effectiveness of Traditional Chinese Medicine (TCM) in treating diarrhea and improving tolerability of pyrotinib. Methods: All patients in the group had diarrhea after taking pyrotinib, and they could not be controlled after previous use of other antidiarrheal drugs (loperamide, Bifidobacterium, montmorillonite powder). All patients were treated with oral TCM (a Chinese herbal formula, one dose per day divided in two times) for 3 weeks. Diarrhea assessment was graded according to NCI-CTCAE v5.0 and quality of life was graded according to EORTC QLQ-C30. The primary endpoint was incidence of grade ≥3 diarrhea. Results: A total of 28 patients were enrolled, and 23 patients completed 3 weeks of TCM treatment and were followed up. The median number of diarrheas was 7 times (4-13), and 15 cases in these 23 patients were ≥grade 3 before treatment with TCM. After treatment with TCM, none of patients had grade 3 diarrhea, and the rate of grade 2 diarrhea was 17.4% (4/23). The scores of global health status/quality-of-life assed with EORTC QLQ-C30 in patients were dramatically improved (40.90+7.68 vs. 62.88+7.15) after treatment with TCM. Most importantly, in the symptom domains scores, we found that TCM treatment did not increase the incidence of constipation, but also significantly improved the fatigue, pain, nausea, vomiting and anorexia of patients. Conclusions: TCM is very effective in the treatment of Pyrotinib related diarrhea, and compared with Western antidiarrheal drugs, it will not produce secondary painful symptoms such as constipation. Clinical trial information: NCT04988165.