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Rooibos is rich in polyphenols with a high anti-oxidant capacity, modulating adrenal steroidogenesis while also influencing cytokine levels. The aim of this study was to investigate Rooibos' immuno-modulating properties, given the interdependence of inflammatory and oxidative stress systems, together with the regulatory function of cytokines in steroidogenesis. Rooibos did not prevent an adequate corticosterone response in rats, with corticosterone and deoxycorticosterone levels significantly increased after 1 hr restraint. IL-6 levels decreased in Rooibos-treated rats while IL-10 (P < 0.05) and IL-10:IL-6 ratios (P < 0.01) increased. Rooibos inhibited glucocorticoid production more significantly in forskolin-stimulated than in basal H295R cells (corticosterone and deoxycorticosterone, P < 0.00001; 11-dehydrocorticosterone, P < 0.01), independent of IL-6 and IL-10. Rooibos therefore modulated the inflammatory response basally and during acute stress. While Rooibos affects steroid hormone biosynthesis, maintaining beneficial glucocorticoid levels and possibly achieving better long-term outcome in terms of glucocorticoid sensitivity, the ability to respond to acute stressors is unlikely to be compromised.