Immunoglobulin A nephropathy (IgAN) is the most common glomerulonephritis worldwide. Xanthohumol (XN) exhibits anti-inflammatory, anti-oxidant, anti-fibrotic, anti-microbial, anti-proliferative, and immunomodulatory effects that all are associated with the IgAN pathogenesis. Our study aims to evaluate the potential impact of XN on the clinical course of IgAN refractory to conventional treatment. Included were five rigorously selected IgAN patients with poor prognosis assessed on the basis of clinical findings and renal biopsy. Patients received XN orally at a daily dose of 2 mg/kg body weight. Biochemical tests were performed the day before the start of XN administration, and then after 2, 4, 12, 24, and 52 weeks of XN administration. XN induced a decrease in daily proteinuria in all patients. Compared to baseline values, at T52 the mean reduction in proteinuria and albumin-creatinine-ratio was 45.3% and 48.4% respectively (p < 0.001 in both cases). Reduction of urine erythrocyturia occurred in four out of five patients. No progression of chronic kidney disease was observed in any patient. No adverse effects of XN were observed, and XN was well tolerated. XN supplementation has potential as an additive treatment for IgAN patients. Moreover, XN appears to be safe and well tolerated.