In relation to the interplay between C-reactive protein (CRP) and its various ligands, including extracellular matrix proteins or plasma proteins, herein we compared the effectiveness of modified CRP (mCRP) in modulation of platelet function under different experimental conditions. mCRP (100 μg/ml) was significantly more effective in stimulation of platelet activation when measured in suspensions of isolated platelets than in whole blood (fraction of CD62-positive platelets was 73.4 ± 5.3 vs. 0.8 ± 1.0% in isolated platelets and 7.0 ± 1.8 vs. 1.3 ± 0.4% in whole blood). Platelet adhesion to fibrinogen was almost seven-fold higher in suspensions of isolated platelets compared to platelet-rich plasma (PRP) (P < 0.005). Furthermore, mCRP enhanced platelet aggregation in a whole blood but it had no effect in PRP. The effectiveness of mCRP in stimulation of platelet response in plasma has been associated with the proportions of gamma globulin and albumin in human serum (rp = 0.78, P < 0.0001 for gamma globulin and Rp = -0.52, P = 0.02 for albumin concentrations; for albumin/gamma globulin ratio rp = -0.72, P < 0.0005). Such associations have been further confirmed by experiments showing that mCRP interacts with some immunoglobulins. Taken together, the modulation of platelet function by mCRP seems to be strongly determined by the presence of the gamma globulin fraction in platelet milieu.