Background: Irritable bowel syndrome (IBS) is a chronic functional gastrointestinal disease presenting clinically by abdominal pain with alteration of bowel habits. Although IBS has uncertain etiology, chronic gut inflammation due to persistent exposure to an infectious agent including Blastocystis sp. was proposed. Aim: to determine the prevalence of Blastocystis hominis infestation in Systemic lupus erythematosus (SLE) patients and determining the immunomodulatory effect of Blastocystis hominis on SLE pathogenesis. Subjects and Methods: A total number of 84 patients attending the SCU hospital outpatient clinics (40 IBS patients / 24 SLE patients / 20 healthy controls) were enrolled in the study and a stool and blood samples were collected. Blastocystis was detected by PCR and serum IL-6 assay by ELISA. Results: Among IBS patients, Blastocystis sp. could be detected at a frequency of 2.5% (1/40), 27.5% (11/40) using direct microscopy and PCR assay respectively while among SLE/IBS patients, it could be detected at a frequency of 8.33% (2/24), 41.66% (10/24). IL-6 assay was higher in PCR positive patients in all study groups. Conclusions: The prevalence of Blastocystis hominis infestation is higher in SLE patients who had IBS compared to IBS patients or asymptomatic controls; with evidence of IL-6 increase in their sera suggesting an immunomodulatory interaction between SLE and Blastocystis hominis.