Hydrolysis of human C-reactive protein (CRP) at pH 4.5 and pH 7.4 with neutrophil-derived lysosomal enzymes yielded 10% trichloroacetic acid soluble peptides (Mr less than 14,000). These peptides inhibited neutrophil superoxide production, chemotaxis, degranulation and phagocytosis at 2 micrograms/ml. This inhibition was not observed with native CRP or intermediate peptides (Mr greater than 14,000). CRP peptides (Mr less than 14,000) also caused a dose-related inhibition of Quin-2 fluorescence indicating interference with intracellular calcium movements during cell activation. These results point to a potential regulatory role for CRP-derived degradation products on neutrophils during inflammation.