During anti-hormonal therapy for prostate cancer, a major clinical problem is the development of androgen-independent disease. The molecular mechanisms underlying the transition to androgen independence are the subject of intense investigation. In many prostate tumors, the activity of the transcription factor EGR1 (early growth response gene 1) is elevated due to overexpression of EGR1 and/or downregulation of the co-repressor, NAB2. We have modeled these alterations by expressing active EGR1 that does not bind NAB co-repressor proteins in human prostate carcinoma cells. We show here that active EGR1 expression enhances the androgen-independent growth of prostate carcinoma cells in vitro and in vivo. Employing RNAi and expression analyses, we show that EGR1 mediates its effects, at least in part, through the AR signaling pathway. These findings support a role for enhanced EGR1 activity in regulating the transition from androgen-dependent to androgen-independent prostate cancer. © 2005 Wiley-Liss, Inc.