Amyloid A (AA) amyloidosis is a severe complication of many chronic inflammatory disorders, including the hereditary periodic fever syndromes. However, in one of these periodic fever syndromes, the hyper IgD and periodic fever syndrome, amyloidosis is rare despite vigorous, recurring inflammation. This hereditary syndrome is caused by mutations in the gene coding for mevalonate kinase, an enzyme of the isoprenoid pathway. In this study, we used a cell culture system with human monocytes to show that inhibition of the isoprenoid pathway inhibits amyloidogenesis. Inhibition of the isoprenoid pathway by lovastatin resulted in a dose-dependent reduction of amyloid formed [53% at 10 microM (P=0.01)] compared with mononuclear cells that are exposed only to serum AA. The inhibitory effects of lovastatin are reversible by addition of farnesol but not geranylgeraniol. Farnesyl transferase inhibition also inhibited amyloidogenesis. These results implicate that the isoprenoid metabolism could be a potential target for prevention and treatment of AA amyloidosis.