This study was undertaken to evaluate the influence of treatment with rifaximin followed by the probiotic VSL#3 versus no treatment on the progression of chronic prostatitis toward chronic microbial prostate-vesiculitis (PV) or prostate-vesiculo-epididymitis (PVE). A total of 106 selected infertile male patients with bacteriologically cured chronic bacterial prostatitis (CBP) and irritable bowel syndrome (IBS) were randomly prescribed rifaximin (200 mg, 2 tablets bid, for 7 days monthly for 12 months) and probiotic containing multiple strains VSL#3 (450 × 10(9) FU per day) or no treatment. Ninety-five of them (89.6%) complied with the therapeutic plan and were included in this study. Group A = "6Tx/6-": treatment for the initial 6 and no treatment for the following 6 months (n = 26); Group B = "12Tx": 12 months of treatment (n = 22); Group C = "6-/6Tx": no treatment for the initial 6 months and treatment in the last 6 months (n = 23); Group D = "12-": no treatment (n = 24). The patients of Groups A = "6Tx/6-" and B = "12Tx" had the highest frequency of chronic prostatitis (88.5% and 86.4%, respectively). In contrast, group "12-": patients had the lowest frequency of prostatitis (33.4%). The progression of prostatitis into PV in groups "6Tx/6-" (15.5%) and "6-/6Tx" (13.6%) was lower than that found in the patients of group "12-" (45.8%). Finally, no patient of groups "6Tx/6-" and "6-/6Tx" had PVE, whereas it was diagnosed in 20.8% of group "12-" patients. Long-term treatment with rifaximin and the probiotic VSL#3 is effective in lowering the progression of prostatitis into more complicated forms of male accessory gland infections in infertile patients with bacteriologically cured CBP plus IBS.