Cross-talk between the estrogen receptor and the mammalian target of rapamycin (mTOR) pathway is one of the mechanisms of endocrine therapy resistance, and the phosphorylated S6 kinase 1(p-S6K1) is known to be a marker of the mTOR pathway activation. The authors assessed the prognostic significance of p-S6K1 according to the hormone receptor (HR) status. The expression of p-S6K1 was evaluated in 304 breast cancer tissues, and the association between its expression and patient outcomes was investigated. Among 197 cases with the HR (+) tumor, 70 (35.5%) were positive for p-S6K1. Most of the patients (97.5%) with the HR (+) tumor received adjuvant endocrine therapy. The expression of p-S6K1 was found to be an independent worse prognosticator affecting overall survival (OS) and breast cancer-specific survival (BCSS) in the HR (+) group (hazard ratio, 2.62; 95% confidence interval [CI], 1.19-5.76; P = 0.017 and hazard ratio, 3.25; 95% CI, 1.20-8.82; P = 0.020, respectively). In the HR (-) group, however, the p-S6K1 expression was not associated with patients' survival. The expression of p-S6K1 is a worse prognostic factor in patients with HR (+) tumors. These results suggest that the p-S6K1 expression might be a marker for endocrine therapy resistance in patients with HR (+) tumors.