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A method is presented for the immunohistochemical localization of Cx-reactive protein in rabbits, based on the use of a defined antiserum and rigorous fixation techniques requisite for this antigen. In animals in which inflammatory lesions and CxRP response were induced by intramuscular injection of typhoid vaccine, Cx-reactive protein was localized only in the area of local inflammation within muscle fibers showing morphologic evidence of necrotic change. Within such altered fibers, CxRP was observed in peripheral segments of myofiber or in subsarcolemmal sarcoplasm, in scattered deposits in sarcoplasm, and in vacuolar inclusions. No CxRP was found at any time in polymorphonuclear or mononuclear cells in the inflammatory lesion, nor in contralateral muscle, regional or distal lymph nodes, liver, spleen, thymus, heart, or kidney, except as traces in lumens of vessels or interstitium. CxRP was first detected in necrotic myofibers at the inflammatory site after a latent period of 8 to 10 hours following injection of the inflammatory stimulus and could be demonstrated in these sites for the 48 hours of the experiment. It could not be observed at the inflammatory site before appearance in the blood. Identical histologic localization in necrotic myofibers at the site of the local lesions was found following induction of granulocytopenia with nitrogen mustard. These findings are consistent with the hypothesis that CxRP is formed locally at the site of inflammation from tissue elements undergoing necrotic change. Alternatively, secondary deposition from the blood at the inflammatory site cannot be excluded, but is considered less likely in view of the failure to obtain evidence of a cellular localization of CxRP in other organs.