Ca 15-3 is an aspecific tumor marker characteristic of cancer proliferation. Elevated serum levels seem to be closely correlated with cancer progression in non-urological tumors. This study assessed the role of Ca 15-3 as an aspecific tumor marker in patients with borderline prostate-specific antigen (PSA) biochemically suspected of prostate cancer (PCa) and with multiple negative prostate biopsies. The study is based on prospective analysis of 103 patients: (a) 33 patients (group A) presented lower urinary tract symptoms secondary to BPH with normal serum PSA values, DRE and TRUS negative for suspected PCa; (b) 31 patients (group B) with histologically diagnosed PCa; (c) 39 patients (group C) with borderline serum PSA values, DRE and TRUS normal, two ultrasound (US)-guided random prostate biopsies negative for PCa. Ca 15-3 was determined in the entire study series by the IRMA method, using as range the values proposed for the investigated non-urological tumors (38 UI/l).Ca 15-3 was within normal range in all group A patients (control), while the values were elevated in 27/31 of group B patients (PCa) and in 11/39 of group C (PCa suspected) patients. A third biopsy was performed in all 39 group C patients with borderline PSA and it was PCa-positive in 13 patients (33.3%, subgroup C3). In this series Ca 15-3 was increased in 9 of 13 patients (subgroup C3alpha), while the remaining four patients (subgroup C3beta) presented values within the normal range. On 26 group C patients who were negative for PCa to third biopsy (subgroup C4), 24 patients had Ca 15-3 levels within normal range (subgroup C4alpha) with histologic findings of BPH in 23 cases and granulomatous chronic prostatitis in one case, while two patients (subgroup C4beta) had elevated Ca 15-3 concentrations associated with lymphoplasmacytic chronic prostatitis. We hypothesize that Ca 15-3, as a specific tumor marker, could be an interesting and inexpensive second step diagnostic tool for PCa in patients with borderline PSA and multiple negative prostate biopsies, as it could indicate whether a repeated biopsy should be performed in a short time, having excluded other concomitant tumors. However, further prospective studies will be necessary to confirm this hypothesis.