Background: Many factors can contribute to male infertility and one of them is presence of high concentration of WBCs in semen which is known as leukocytospermia. Clusterin is a seminal plasma protein with proposed cytoprotective role against oxidative stress and other harmful effect of leukocytospermia. Objective: This study aims to investigate the role of seminal plasma clusterin in infertility associated with leukocytospermia. Patients and methods: A prospective case-control study was conducted on 96 men recruited from Mansoura University Hospitals Andrology outpatient clinic. We divide them into four groups: fertile without leukocytospermia (control group), fertile with leukocytospermia group, infertile without leukocytospermia group and infertile with leukocytospermia group. Results: The seminal plasma levels of clusterin concentration were found to be significantly reduced in all groups in comparison to the control group (P<0.0001). Also comparing both infertile groups showed significant reduction in clusterin in the group associated with leukocytospermia (P=0.0034). Moreover, clusterin showed high significant positive relationship with semen parameters, alpha-glucosidase, acrosin activity index and total antioxidant capacity. However, it showed significant negative relationship with MDA (p < 0.0001). These results support the protective role of clusterin against the oxidative stress in semen, which represents one of the most important mechanisms by which leukocytospermia could affect semen quality and interfere with fertility function. Conclusions: Clusterin has an important sperm protective role against oxidative stress and seminal plasma clusterin level is significantly reduced in infertile patients with leukocytospermia, which may explain one of the mechanisms of how leukocytospermia interferes with the fertility function.