Inflammatory diseases are commonly associated with depressed mood. This association may be influenced by the production of proinflammatory cytokines. Accordingly, we assessed whether cytokine levels and mood (measured with the profile of mood states) could be altered by a mild, non-sickness inducing, acute inflammatory stimulus. Using a randomised placebo-controlled, double-blind design, 30 healthy male volunteers were injected with Salmonella typhi vaccine or placebo. Assessments of mood, symptoms of illness and temperature were made at baseline and at 1.5, 3, and 6 h post-injection. Plasma concentrations of interleukin-6 (IL-6), interleukin-1 receptor antagonist (IL-1Ra), and tumour necrosis factor-alpha (TNF-alpha) were assessed at baseline and 3 h post-injection. No significant symptoms of illness were reported in either group. Mood was more negative following injection in the vaccine than the placebo group, and the vaccine group experienced a 106% increase in IL-6 concentration. Negative changes in mood following injection were significantly correlated with increases in IL-6 production. No changes in TNF-alpha or IL-1Ra concentration were recorded in either group. It is concluded that S. typhi vaccination may be a useful model of mild inflammatory challenge, producing a significant transient cytokine-induced decrease in mood in the absence of any febrile response. Implications for depressed mood in physical illness are discussed.