Purpose: This study was conducted to evaluate the incidence of prostate cancer (PCa) in Iranian male patients with increased prostate-specific antigen (PSA), and normal or abnormal digital rectal examination (DRE) that underwent prostate biopsy. Materials and methods: From March 2006 to April 2009, a total of 346 consecutive males suspected of having PCa due to increased PSA levels underwent transrectal ultrasonography (TRUS)-guided sextant biopsy of the prostate. The total PSA (tPSA), demographic data, incidence of PCa, benign prostate hyperplasia (BPH), and prostatitis were assessed. Results: The patients were divided into two groups according to their PSA values (group A serum tPSA level, 4-10 ng/mL; group B serum tPSA level, 10.1-20.0 ng/mL). Of the 346 biopsied cases, 193 cases (56%) had PCa, 80 cases (23%) had BPH, and 73 cases (21%) had prostatitis. The mean PSA and the age of the carcinoma group were significantly higher than those of the benign group (P , 0.01). The biopsy results were grouped as PCa, BPH, and prostatitis. Incidence of PCa for group A and group B cases were 115 cases (51%), and 78 cases (65%), respectively. In the case of PCa, BPH, and prostatitis, the mean PSAs were 10.02 ng/mL, 8.76 ng/mL, and 8.41 ng/mL, respectively (P , 0.40). Conclusion: TRUS-guided prostate biopsy and interpretation by a skilled team is highly recommended for early detection of PCa or its ruling-out. It seems that a PSA cutoff value of 4 ng/mL may be applied to the Iranian population. Although the chance of PCa is high in the PSA levels of 4-10 ng/mL, the combination of some data, like age and prostate volume, can decrease the rate of unnecessary prostate biopsies. We recommend prostate biopsy when PSA and/or DRE is elevated in symptomatic patients with obstructive and/or irritative lower urinary tract symptoms (LUTS) such as dysuria, frequency, or nocturia. Due to the very high incidence of PCa in the patients with PSA greater than 10 ng/mL, TRUS-guided biopsy is indicated, whatever the findings on DRE and/or LUTS, since the PCa detection rate is high.