The hyper-IgD and periodic fever syndrome (HIDS) and familial Mediterranean fever (FMF) are both characterized by attacks of periodic fever accompanied by acute phase responses that are substantially higher in HIDS than in FMF. To determine whether this difference could be due to differences in production of acute phase protein-inducing mediators, we studied PBMC from HIDS and FMF patients in the inactive phase of disease. Unstimulated PBMC from patients with inactive HIDS released significantly more IL-1 beta, IL-6, and TNF-alpha than did PBMC from patients with FMF, but unstimulated PBMC from the latter group released significantly more IL-1 beta and IL-6 compared with controls. Conditioned medium (CM) derived from PBMC of patients with inactive HIDS induced significantly greater CRP production and significantly higher mRNAs for CRP and SAA in Hep3B cells than did CM derived from the PBMC of patients with inactive FMF. Stimulation of PBMC with LPS led to further increases in cytokine production and in acute phase protein-inducing ability in both patient groups and in controls. These findings suggest that the greater acute phase response seen in HIDS compared with FMF reflects greater production of acute phase protein-inducing cytokines in the former patients and indicates that PBMC from inactive HIDS patients are already activated in vivo. Finally, the finding of both quantitative and qualitative differences in cytokine production by unstimulated PBMC from HIDS and FMF patients supports the likelihood of different pathogeneses of these diseases.