The hyperimmunoglobulinemia D syndrome (HIDS) is an autosomal recessive disorder characterized by recurrent febrile attacks with abdominal, articular, and skin manifestations. Apart from elevated immunoglobulin D (IgD) levels (>100 IU/ml), there are high IgA levels in the majority of cases. Mutations in the gene encoding mevalonate kinase constitute the molecular defect in HIDS. The cause of elevated IgA concentrations in HIDS patients remains to be elucidated. We studied the hyper-IgA response in serum of a group of HIDS patients. Elevated IgA concentrations result from increased IgA1 concentrations. IgA and IgA1 concentrations correlated significantly with IgD concentrations, and levels of IgA polymers were significantly higher than the levels in healthy donors. These results indicate a continuous, presumably systemic, stimulation of IgA in HIDS patients.