Prostate cancer is the most commonly diagnosed malignancy in male populations in the Western world. The KLK15 gene, the newest member of the kallikrein family, is expressed in the prostate gland. The purpose of this study is the expression analysis and the clinical evaluation of the KLK15 mRNA spliced variants in prostate cancer (CaP) and benign prostatic hyperplasia (BPH) patients. Total RNA was isolated from 104 CaP and BPH tissue specimens. After testing the quality of the RNA, cDNA was produced by reverse transcription, and PCR was performed for the amplification of the KLK15 mRNA transcripts. GAPDH and HPRT genes were used as endogenous controls. Our data revealed that mRNA spliced variants of KLK15 were differentially expressed in prostate tissue specimens. Analysis of data showed a statistically significant (P < 0.001) increase in the frequency of overexpression of KLK15 transcripts encoding for both the active isoform and for the isoform 3 in CaP compared to BPH samples. Furthermore, KLK15 transcripts were found to be highly expressed in more aggressive tumors (P = 0.017). These results suggest that KLK15 expression analysis could be employed as a valuable tool for the discrimination between BPH and CaP tissue specimens and as an unfavorable prognostic marker for prostate cancer. (Cancer Sci 2010; 101: 693-699) P rostate cancer (CaP) is the most common non-skin male malignancy, accounting for almost 33% of all cancer incidents. Also, it is the second-most common cause of cancer-related deaths in most Western countries.(1,2) Although many risk factors, such as alterations in androgen biosynthesis and metabolism, and diet and chronic inflammation, have been associated with the disease, the etiology of prostate cancer remains uncertain.(1,3,4) The most common form of the disease is sporadic prostate cancer, which is expected to be developed by non-random somatic genome alterations such as loss or gain of chromosomal regions (6q, 7q, 8p), abnormal DNA methylation, mutations of oncogenes (EGFR, MYC) and tumor suppressor genes (NXK3.1, GSTP1), and alterations regarding the androgen receptor (AR).(2,5-7) AR is an intracellular ligand-dependent transcription factor, which plays an essential role in the survival and growth of prostate cells, as well as in the initiation and the progression of prostate tumors. As a result, the disease treatment aims at the regulation and manipulation of the AR metabolic pathway. However, AR function evolves as the cell changes toward a clinical androgen-depletion independent state. (8,9) Recently published data show that benign prostatic hyperplasia (BPH) occurs to about 8% of men aged from 31 to 40 years, to one-quarter of men in their 50s, to one-third of men in their 60s, to about half of all men aged 80 years or older and increases to about 90% by the ninth decade of life. (10) Since the discovery of prostate-specific antigen (PSA) also known as, kallikrein (KLK) 3 routine PSA testing has become the mainstay of prostate cancer detection.(11) However, PSA lacks diagnostic sp...