In the search for strategies which might help in the elucidation of molecular mechanisms involved in the red blood cell (RBC) invasion by P. falciparum merozoites, and with the specific aim of establishing whether synthetic peptides derived from selected parasite proteins bind to human RBCs, 26 different peptides were chemically synthesized and radiolabeled. It was found that the peptides could be grouped, according to their RBC-binding kinetics, into high, medium and low binding activity. A correlation was detected between the high binding activity of a peptide and the presence of either a KEK motif (or its variants LEK or KEL) or a NVXAA (where X is V or Y). Peptides with medium or low binding activities did not possess either of these two consensus sequences. Selective modification of amino acids within the KEK motif diminished their uptake or binding capacity. Competitive inhibition assays of labeled or unlabeled peptide demonstrated a correlation between the presence of KEK or NVXAA motifs and a high binding activity of a peptide. Invasion-inhibition studies showed a direct correlation between a peptide's binding activity and inhibitions of human RBC reinvasion. Other experiments showed that high binding activity peptides show a decreased uptake with related and nonrelated human erythrocytes.