Activation of the immune system elicits several behavioral changes that are collectively called sickness behavior and consists in a strategy to overcome infection. Sleep deprivation can increase susceptibility to pathogens and to behavioral alterations. Thus, the present study aimed to determine how paradoxical sleep deprivation (PSD) affects the behavioral and neurochemical responses to lipopolysaccharide (LPS, potent activator of the immune response). Adult inbred mice were paradoxical sleep deprived (72 h), whereas the control group was kept in their home cages. Both groups received either an injection of saline or LPS (5, 10 or 20 microg/animal ip) before behavioral tasks and tissue collection. During the recovery sleep period, LPS provoked a strong inhibition of sleep rebound due to a suppression of paradoxical sleep. PSD increased the susceptibility of mice to LPS-induced immobility in the open field, which was capable of affecting the anxiety-like behavior also. These altered behavioral responses to LPS were accompanied by reduction in dopamine turnover within the striatum and increased expression of cyclooxygenase-2 in the cortex. The study provides some insights into how the sleep-wake cycle affects the expression of sickness behavior induced by LPS.