Background: The aim of this study was to investigate the immunohistochemical expression of ribosomal protein (RP) S6-pS240 in non-special type invasive breast cancer in relation to other prognostic markers and gain new insights to facilitate more individualized treatment. Methods: The following clinical and histopathological parameters of 120 patients were determined: S6-pS240 expression, age, menopausal status, tumor size and grade, TNM stage, Nottingham Prognostic Index (NPI), lymph node stage, estrogen and progesterone receptor (ER/PR) expression, HER2/neu amplification, lymphovascular invasion, and proliferative index as measured by Ki-67. Treatment protocol and disease-free survival were evaluated accordingly. Results: Significant positive correlations were seen between S6-pS240 expression and Ki-67 values (rho = 0.530, p < 0.001), and NPI (rho = 0.370, p < 0.001) and HER2/neu amplification (rho = 0.368, p < 0.001). A negative correlation was found between S6-pS240 and ER/PR expression (rho = 0.362, p < 0.001). Patients with negative RP S6-pS240 expression had significantly longer disease-free survival (log-rank test, p = 0.005). Conclusion: Immunohistochemical analysis of RP S6-pS240 is a valuable additional prognostic marker in patients with invasive breast cancer. Routine use of S6-pS240 immunohistochemistry is recommended.