C-reactive protein (CRP) is an acute-phase reactant which has been found deposited at sites of inflammation and tissue destruction. Experimental allergic encephalomyelitis (EAE) is a demyelinating disease of the central nervous system characterized by inflammatory cellular infiltrates. This study describes the CRP response and the deposition of CRP in the spinal cords of rabbits with EAE. EAE was induced by a single injection of rabbit spinal cord in Freund's complete adjuvant. Serum CRP levels in experimental and adjuvant control rabbits showed cyclic elevations. An additional increase in levels of CRP in the serum was observed in the experimental group coincident with the onset of clinical disease. Deposition of CRP in spinal cord lesions of six of nine animals with EAE was demonstrated by direct immunofluorescence. CRP was seen around and within a small proportion of the cells in the acute inflammatory lesion. The amount of CRP deposition was most closely correlated with the proportion of polymorphonuclear leucocytes (PMN) in the infiltrate. No staining was observed in control animals, in experimental animals prior to the onset of clinical signs of EAE, or in clinically affected animals with exclusively mononuclear infiltration. The demonstration of CRP and PMN in acute lesions of rabbits with EAE may reflect a role for humoral mediators of inflammation in this disease.