We aimed to assess protein expressions of p16 and pRB in breast cancer and explore the clinicopathologic implications. Tissue microarray (TMA) was constructed with 406 cases of breast cancer. The cases were subgrouped into luminal A, luminal B, HER-2, and triple negative breast cancer (TNBC) based on the results of immunohistochemical stains for ER, PR, HER-2, and Ki-67 and fluorescent in situ hybridization (FISH) for HER-2. One hundred and sixty-eight cases were allocated to the subgroup luminal A; 87 cases to the luminal B; 32 cases to the HER-2; and 119 cases to the TNBC. The TNBC group showed the highest negative rate for p16, and the luminal B and HER-2 groups showed the highest positive rate for p16 (P< 0.001). Alteration of p16 was the highest in the luminal B and HER-2 groups, and pRB expression rate was the highest in the HER-2 group and lowest in the luminal A group. In addition, p16 (+)/pRB (+) type was the most common in the luminal B group, p16 (+)/pRB (-) in the luminal A group, and p16 (-)/pRB (+) in the TNBC group (P< 0.001). Altered p16/pRB (+) and non-altered p16/pRB (+) type was the most common in the luminal B, and altered p16/pRB (-) and non-altered p16/pRB (+) type was the most common in the luminal A (P< 0.001). Alteration of p16 was correlated with higher Ki67 labeling index (LI)(P= 0.013), and p16 negativity was correlated with ER negativity (P= 0.002), PR negativity (P= 0.004), and higher Ki67 LI (P< 0.001). pRB positivity was correlated with PR negativity (P= 0.009), HER-2 positivity (P= 0.001), and higher Ki-67 LI (P< 0.001). In luminal group A, p16 alteration was correlated with shorter DFS in univariate analysis (P= 0.024). In conclusion, Expression rates of p16 and pRB differ according to the molecular subgroups of breast cancer and they subsequently correlate with clnicopathologic factors.