Bacterial endotoxin and interleukin-1 (IL-1) challenge induce a constellation of symptoms associated with illness. While such treatment may result in anhedonia, it is often difficult to dissociate this effect from the anorexia induced by these agents, particularly in paradigms that involve appetitive motivation. The present investigation assessed the effects of several systemically administered cytokines (IL-1beta, IL-2 and IL-6) on reward processes by evaluating responding for rewarding intracranial self-stimulation (ICSS) from the lateral hypothalamus. Systemic administration of interleukin-2 (IL-2) disrupted responding from the medial forebrain bundle, and this disturbance persisted as long as 1 week following initial cytokine treatment. In contrast to reinforced responding, following IL-2 treatment, non-reinforced behavior was unaffected, indicating that the cytokine did not provoke reward-unrelated performance deficits. It was suggested that the effects of IL-2 on ICSS likely do not involve motoric, soporific, attentional or cognitive changes, but instead involve specific actions on motivational arousal. Although IL-6 was previously found to produce mesolimbic dopamine (DA) changes as marked as those induced by IL-2, systemic IL-6 treatment did not influence responding for rewarding brain stimulation. Likewise, although IL-1 at the dosage used reliably induces sickness behavior, responding for rewarding brain stimulation was unaffected. Thus it seems that anhedonia is not necessarily a component of the sickness response associated with IL-1 treatment.