Human C-reactive protein (CRP) is a clinically important classical acute phase protein. Although CRP has been reported to bind with many nucleated cells, the direct binding of CRP to erythrocytes in diseases remains largely unexplored. The main focus of the present study was to investigate the binding of disease-specific CRP to erythrocytes of same patients. Distinct molecular variant of disease-specific CRP was affinity purified from sera of malaria patients (CRPMal). This CRP showed strong binding with malaria erythrocytes (RBCMal) as confirmed by flow cytometric analysis (FACS), enzyme-linked immunosorbent assays (ELISA), and radio binding assays. Calcium and phosphoryl choline (PC) were found to be essential for this interaction. A 2.3-fold increased binding of induced CRP to RBCMal as compared to normal erythrocytes (RBCN) confirmed disease-specificity. Preincubation of RBCMal with unconjugated CRP showed 3–5 fold inhibition. The association constant of CRP and RBCMal was 4.7 × 106 cpm/μg with the corresponding number of receptors/cell being 4.3 × 105. The effector function of CRPMal has been demonstrated by its potency to activate the complement pathway. An optimal dose of 10 μg/ml of CRP induced three-fold higher hemolysis of patient erythrocytes as compared to RBCN. These studies provide direct evidence for an important phagocytic functional interaction of this acute-phase protein by triggering the CRP-complement pathway after the binding of CRPMal with RBCMal. Hemolysis as triggered by this pathway may be one of the causative factors of anemia, a common clinical manifestation of this disease.