OBJECTIVE: To investigate differences in gene expression in different zones of the prostate by microarray analyses, to better understand why aggressive tumours predominantly occur in the peripheral zone (PZ), whereas benign prostatic hyperplasia (BPH) occurs almost exclusively in the transition zone (TZ). MATERIALS AND METHODS: Expression profiling of both prostate zones was done by microarray analysis. Reverse transcription-polymerase chain reaction (RT-PCR) of the top 18 genes confirmed the microarray analyses. RT-PCR with common cell-type markers indicated that the differential expression between the zones was not caused by an unequal distribution of different cell types. Primary stromal and epithelial prostate cells were used to study cell type expression in the 12 highest differentially expressed zonal-specific genes. RESULTS: In all, 346 genes were identified as preferentially expressed in the TZ or PZ. A few of the TZ-specific genes, including ASPA, FLJ10970 and COCH, were also stroma-specific. Comparisons with other microarray studies showed that gene expression profiles of prostate cancer and BPH correlate with the expression profiles of the PZ and TZ, respectively. CONCLUSION: Gene expression differs between the PZ and TZ of the prostate, and stromal-epithelial interactions might be responsible for the distinct zonal localization of prostate diseases.