About a quarter of familial Mediterranean fever (FMF) patients are partially or totally resistant to colchicine. A previous observation reported that acute attacks may be shortened by administration of interferon alpha (IFN). We designed a double-blind, placebo-controlled trial to test our initial observations of a beneficial response with IFN in FMF attacks. We treated 34 acute abdominal attacks with IFN 5 million IU or placebo sc in the early phase of the attack. Leucocytes, thrombocytes, the erythrocyte sedimentation rate, fibrinogen, C-reactive protein (CRP), serum amyloid A protein (SAA), haptoglobin, transferrin, IL-1beta and TNF-alpha were measured at hours 0, 6, 12, 24 and 48. The median time to recovery in those treated with IFN and placebo was not significantly different, while the leucocytosis and high levels of fibrinogen were significantly more prolonged in placebo-treated patients. CRP and SAA were extremely elevated and peaked at 24h, remaining less marked in the IFN-treated patients but the difference was not statistically significant. Observations regarding the other parameters were unremarkable. Although there were some clues indicating a depressed inflammatory response with IFN, we could not demonstrate a definitive effect of this agent in this double-blind trial. The drug may suppress the acute inflammation of FMF only if administered at the earliest phase. CRP and SAA may be more sensitive indicators of an attack than ESR or fibrinogen.