The immunolocalization of the p16 and cdk4 proteins was investigated in 65 retinoblastoma gene product (pRB)-positive and 20 pRB-negative breast carcinomas. These proteins were expressed in similar lesions in 84.6% of the pRB-positive and 100% of the pRB-negative carcinomas. Diffuse expression of p16 was observed in 73.8 and 70.0% of the pRB-positive and -negative cases, respectively. cdk4 and p16 expression was significantly more heterogeneous in tumors of larger sizes and/or at higher stages. These findings suggest that p16 can be induced regardless of pRB status and Rb gene function in primary breast carcinoma and that it modulates the cell cycle progression in association with cdk4.