Migraineous and non-migraineous headache is reported to be at highest intensity after an infection. This study investigated whether activation of the immune system can induce hyperalgesia in intracranial capsaicin sensitive afferents. The effects of intraperitoneal injected lipopolysaccharides (LPS) on behavior and c-fos expression in the trigeminal nucleus caudalis layer I, II (TNC I,II) elicited by intracisternally applied capsaicin were studied. Low concentrations of LPS potentiated capsaicin-induced immobilization behavior without affecting c-fos expression in the TNC I,II. Large amounts of LPS however increased the number of capsaicin-induced c-fos positive cells in the TNC I,II. These effects of LPS on capsaicin sensitive afferents are probably mediated by cytokines that act at peripheral vagal nerves, central brain regions or via direct actions of cytokines on capsaicin sensitive afferent nerve terminals. The hyperalgesic action of LPS on intracranial trigeminal and possibly other capsaicin sensitive afferents of the head may explain why different types of infections are accompanied by headache and why migraineous and non-migraineous headache is of highest intensity after an infection.