OBJECTIVE: Programmed cell death-1 (PD-1, encoded by PDCD1) regulatory network participates in glioblastoma multiforme development. However, such a network in trastuzumab-resistant human epidermal growth factor receptor 2-positive (HER2+) breast cancer remains to be determined. Accordingly, this study was aimed to explore the PD-1 regulatory network responsible for the resistance of breast cancer cells to trastuzumab through a bioinformatics approach. METHODS: The study used data mining tools like cBioportal and OMIM to identify genes involved in the programmed cell death-1-trastuzumab resistance regulatory network. The network was further examined using various tools like WebGestalt, DAVID, STRING, Cytoscape, CytoHubba, GEPIA, TNMPlot, and ROCPlot. RESULTS: The PDCD1 regulatory network in trastuzumab-resistant HER2+ breast cancer is linked to Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), interleukin (IL)-10, protein tyrosine phosphatase receptor type C (PTPRC), and FCGR2B. These factors have a significant prognostic power in pathological complete response in breast cancer patients treated with trastuzumab. Infiltration of B cells, CD8+ cells, CD4+ cells, neutrophils, dendritic cells, macrophages, and regulatory T cells is directly correlated with PTR expression. CONCLUSION: The study identified four genes (CTLA4, IL10, PTPRC, and FCGR2B) that are linked to the regulatory network of PD-1 in trastuzumab-resistant HER2+ breast cancer cells. Further research is needed to develop the therapeutic target against trastuzumab resistance in HER2+ breast cancer.