Abstract Background To identify the factors influencing pyrotinib-induced severe diarrhea and to establish a risk prediction nomogram model. Methods The clinical data of 226 patients received pyrotinib from two medical institutions from January 2019 to December 2023 were analysed retrospectively. A training set was made up of 167 patients from Hainan Cancer Hospital, and the external validation set was made up of 59 patients from Hainan West Central Hospital. Univariate and multivariate logistic regression analysis were used to identify independent factors influencing pyrotinib-induced severe diarrhea, and a risk prediction nomogram model was constructed, which was verified on patients in the external validation set. Results History of adverse reactions (ADRs), initial dose of pyrotinib, combination with capecitabine, thrombocytopenia, aspartate transaminase (AST), and use of probiotics or other drugs that regulate the gut microbiota were identified as independent influencing factors for pyrotinib-induced severe diarrhea (all P