The functional similarities between C-reactive protein (CRP) and immunoglobulin raised the possibility that modified CRP might resemble immunoglobulin in its activating effects upon the human platelet. Thermally-aggregated CRP (H-CRP), but not unmodified CRP, induced reactions of aggregation and secretion from isolated platelets; maximum responses occurred with less than 50 microgram/ml H-CRP and were similar to responses mediated by thermally-aggregated human IgG (AHGG). Platelet activation induced by H-CRP was sensitive to the presence of EDTA and dibucaine, required metabolic energy and was inhibited by increased levels of cAMP. Like AHGG, H-CRP acted synergistically with other platelet stimulators, although on a weight basis H-CRP appeared approximately ten- to twenty-fold more effective than AHGG. Complexes formed between CRP and certain of its polycationic ligands (PLL and protamine) shared platelet activating properties with H-CRP, whereas complexes of CRP and CPS did not. These data point to the ability of appropriately modified CRP to stimulate or enhance platelet responsiveness, and taken together with those reactivities described previously between modified CRP and certain lymphocytes, phagocytes, and the complement system, support the concept that CRP can initiate biological activities similar to those mediated by immunoglobulin.