Tamoxifen treatment is important assistant for estrogen‐receptor‐positive breast cancer (BRCA) after resection. This study aimed to identify signatures for predicting the prognosis of patients with BRCA after tamoxifen treatment. Data of gene‐specific DNA methylation (DM), as well as the corresponding clinical data for the patients with BRCA, were obtained from The Cancer Genome Atlas and followed by systematic bioinformatics analyses. After mapping these DM CPG sites onto genes, we finally obtained 352 relapse‐free survival (RFS) associated DM genes, with which 61,776 gene pairs were combined, including 1,614 gene pairs related to RFS. An 11 gene‐pair signature was identified to cluster the 189 patients with BRCA into the surgical low‐risk group (136 patients) and high‐risk group (53 patients). Then, we further identified a tamoxifen‐predictive signature that could classify surgical high‐risk patients with significant differences on RFS. Combining surgical‐only prognostic signature and tamoxifen‐predictive signature, patients were clustered into surgical‐only low‐risk group, tamoxifen nonbenefit group, and tamoxifen benefit group. In conclusion, we identified that the gene pair PDHA2–APRT could serve as a potential prognostic biomarker for patients with BRCA after tamoxifen treatment.