BACKGROUND: The hyper-IgD and periodic fever syndrome (HIDS) is characterized by recurrent attacks of fever, abdominal distress, and arthralgia and is caused by mevalonate kinase mutations. OBJECTIVE: To ascertain the role of mevalonate kinase and the usefulness of molecular diagnosis in HIDS. DESIGN: Cross-sectional study. SETTING: The international Nijmegen HIDS registry. PATIENTS: 54 patients from 41 families who met the clinical criteria for HIDS. MEASUREMENTS: Clinical symptoms and signs, immunoglobulin concentration, leukocyte count, erythrocyte sedimentation rate, mutation analysis, and mevalonate kinase enzyme activity assay. RESULTS: There were two groups of patients: 41 patients with mevalonate kinase mutations (classic-type HIDS) and 13 patients without mutations (variant-type HIDS). Patients with classic-type HIDS had a lower mevalonate kinase enzyme activity, a higher IgD level, and more additional symptoms with attacks. The IgD level did not correlate with disease severity, mevalonate kinase enzyme activity, or genotype. CONCLUSION: Genetic heterogeneity exists among patients with a clinical diagnosis of HIDS.