Progression to androgen independence (AI) is the main cause of death in prostate cancer. Our prior differential gene expression studies by microarray analysis in progressive prostate cancer cell line model identified dysregulation of protein kinase C μ (PKCμ) expression in prostate cancer. In this study, quantitative ribonuclease protection assay and immunoblot analysis demonstrate down regulation of PKCμ at transcription and translational level, respectively, in AI C4-2 cells compared to its parental androgen dependent (AD) LNCaP prostate cancer cells. Significantly lower PKCμ kinase activity was confirmed in C4-2 cells by in vitro kinase assay. Immunohistochemical studies of prostate cancer tissue from patient progressing to AI prostate cancer demonstrated that PKCμ expression is decreased in 100% of AI human prostate cancers. The consistent down regulation of PKCμ in cell line models and human prostate cancer tissues suggests a possible functionally significant role for PKCμ in progression to AI in prostate cancer.