The inflammatory response in infectious and autoimmune diseases is regulated by the balance between pro- and anti-inflammatory cytokines. The IL-1 complex contains polymorphic genes coding for IL-1α, IL-1β and IL-1Ra. The IL-1Ra (variable number of tanden repeat) VNTR polymorphism has been shown to influence the capacity to produce IL-1β and IL-1Ra after in vitro stimulation. Allele 2 of this polymorphism is associated with a number of inflammatory diseases. To determine the impact of the IL-1Ra polymorphism on in vivo human cytokine synthesis, we used a yellow fever vaccination model for the induction of cytokine synthesis in healthy volunteers. Two different yellow fever vaccines were used. After administration of the RKI vaccine (34 volunteers), plasma TNF-α concentration increased from 13·4 ± 0·9 pg/ml to 23·3 ± 1·1 pg/ml (P < 0·001), and plasma IL-1Ra concentration increased from 308 ± 25 pg/ml to 1019 ± 111 pg/ml (P < 0·001), on day 2. Using Stamaril® vaccine, no increase in the plasma concentrations of either TNF-α or IL-1Ra could be detected (n = 17). Only the RKI vaccine induced TNF-α synthesis after in vitro stimulation of MNC. Carriers of allele 2 of the IL-1Ra polymorphism had increased baseline concentrations of IL-1Ra (350 ± 32 pg/ml) compared with non-carriers (222 ± 18 pg/ml, P < 0·001), and decreased concentrations of IL-1β (0·9 ± 0·2 pg/ml for carriers versus 2·8 ± 0·7 pg/ml for non-carriers, P = 0·017). After yellow fever vaccination (RKI vaccine), no significant differences in the increase of IL-1Ra plasma levels were detected between carriers and non-carriers of allele 2 of the IL-1Ra gene polymorphism. This is the first study to examine the influence of this genetic polymorphism on in vivo-induced human IL-1β and IL-1Ra synthesis. Baseline concentrations of IL-1Ra and IL-1β were significantly influenced by the IL-1Ra polymorphism. No influence of the IL-1Ra polymorphism on the in vivo-induced production of IL-1Ra and IL-1β could be detected.