BACKGROUND miR‐21 has been recognized as an “onco‐microRNA” with the activity of negatively modulating the expression of tumor‐suppressor genes. However, its role in prostate cancer (CaP) has not been well‐documented. We designed this study to assess the potential function of serum miR‐21 in the progression of CaP. METHODS Serum samples of 56 patients, including 20 patients with localized CaP, 20 with androgen‐dependent prostate cancer (ADPC), 10 with hormone‐refractory prostate cancer (HRPC), and 6 with benign prostatic hyperplasia (BPH), were collected for the measurement of miR‐21. The 10 HRPC patients were administered docetaxel‐based chemotherapy. Quantification of miR‐21 was assayed by specific TaqMan qRT‐PCR. RESULTS Serum miR‐21 level was found to correlate to serum PSA level in patients with ADPC and HRPC, P = 0.012 and 0.049, respectively. There was no significant difference in serum miR‐21 level between BPH, localized CaP and ADPC with PSA level <4 ng/ml. Higher levels of miR‐21 were detected in patients with HRPC and ADPC with PSA level >4 ng/ml. Six of the 10 HRPC patients reached partial remission with a decreased PSA level of >50% after chemotherapy. Serum miR‐21 levels were higher in patients who were resistant to docetaxel‐based chemotherapy when compared to those sensitive to chemotherapy, P = 0.032. CONCLUSIONS Serum miR‐21 levels are elevated in HRPC patients, especially in those resistant to docetaxel‐based chemotherapy. It may be applicable as a marker to indicate the transformation to hormone refractory disease, and a potential predictor for the efficacy of docetaxel‐based chemotherapy. Prostate 71:326–331, 2011. © 2010 Wiley‐Liss, Inc.