Clinical features of certain immune-inflammatory disorders such as rheumatoid arthritis and asthma exhibit diurnal fluctuation, which could be related to diurnal rhythmicity of pro-inflammatory cytokine production. To investigate the latter, the authors performed measurements of lipopolysaccharide (LPS)-stimulated whole blood, interferon γ (IFN-γ), tumour necrosis factor α (TNF-α), interleukin 1 (IL-1) and IL-12 production in 13 healthy volunteers over 24 h. These cytokines exhibited distinct diurnal rhythms that peaked in the early morning and were inversely related to the rhythm of plasma cortisol. Elevation of plasma cortisol within the physiological range by administration of cortisone acetate, 25 mg at 21.00, markedly suppressed IFN-γ, TNF-α, IL-1 and IL-12 production, but not the later early morning rise of endogenous plasma cortisol. Suppression of cytokine production was temporally dissociated from changes in numbers of circulating mononuclear cells. Regulation of pro-inflammatory cytokine production by plasma cortisol has potential therapeutic implications. In contrast to standard schedules, a small, late evening, dose of glucocorticoid to suppress the diurnal increase in pro-inflammatory cytokine production could alleviate early morning inflammatory symptoms and minimize side-effects.