Chronic prostatitis (CP) is a common inflammatory condition of the prostate that is estimated to effect 2-10% of the world’s male population. It can manifest as perineal, suprapubic, or lower back pain and urinary symptoms occurring with either recurrent bacterial infection (chronic bacterial prostatitis [CBC]) or in the absence of evidence of bacterial infection (chronic pelvic pain syndrome [CPPS]). Here, we report a case of a 39-year-old patient displaying symptoms of CP in which a bacteriophage-derived muralytic enzyme (endolysin) was successfully used to resolve the disease. Bacteriological analysis of the patient’s prostatic secretion and semen samples revealed a chronic Enterococcus faecalis prostate infection, supporting a diagnosis of CBP. The patient’s E. faecalis strain was resistant to several antibiotics and developed resistance to others during the course of treatment. Previous treatment with multiple courses of antibiotics, bacteriophages, probiotics, and immunologic stimulation had failed to achieve long term eradication of the infection or lasting mitigation of the symptoms. A seven-day course of treatment with the endolysin resulted in the elimination of the E. faecalis infection to below culturally detectable levels, and the abatement of symptoms to near normal levels. Furthermore, during the endolysin treatment, the patient experienced no untoward reactions. The present report represents the first clinical demonstration of the efficacy of a bacteriophage endolysin in the management of a recalcitrant systemic infection.