Data have suggested that the molecular features of breast cancer are important determinants of outcome; however, few studies have correlated these features with locoregional recurrence (LRR). In the present study, we evaluated estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) as predictors of LRR in patients with lymph node-negative disease and tumors < or = 1cm, because these patients often do not receive adjuvant chemotherapy or trastuzumab. The data from 911 patients with stage T1a,bN0 breast cancer who had received definitive treatment at our institution between 1997 and 2002 were retrospectively reviewed. We prospectively analyzed ER/PR/HER2 expression from the archival tissue blocks of 756 patients. These 756 patients represented the cohort for the present study. With a median follow-up of 6.0 years, the 5- and 8-year Kaplan-Meier LRR rate was 1.6% and 5.9%, respectively, with no difference noted in those who underwent breast conservation therapy vs. mastectomy (p=.347). The 8-year LRR rates were greater in the patients with ER-negative (10.6% vs. 4.2%, p=.016), PR-negative (9.0% vs. 4.2%, p=.009), or HER2-positive (17.5% vs. 3.9%, p=0.009) tumors. On multivariate analysis, ER-negative and PR-negative disease (hazard ratio, 2.37; p=.046) and HER2-positive disease (hazard ratio, 3.13, p=.016) independently predicted for LRR. Patients with ER/PR-negative or HER2-positive T1a,bN0 breast cancer had a greater risk of LRR. Therapeutic strategies, such as the use of chemotherapy and/or anti-HER2 therapies, should be considered for future clinical trials for these patients.