Six peptides, A, B1, B, C, D and E, derived from the primary sequence of Schistosoma mansoni glyceraldehyde 3-phosphate dehydrogenase (SG3PDH) were selected based on lowest homology to human glyceraldehyde 3-P dehydrogenase (G3PDH), multimerized in dipeptidic multiple antigen peptide (D-MAP) constructs and used for the immunization of BALB/c mice. Tetrabranched D-MAPs A-B, B1-C and D-E and the bis-D-MAP B-E elicited strong cell-mediated and antibody responses against immunogen, unit peptides and their cognate sequences in the native and denatured protein. D-MAP A-B induced protection against challenge infection. Immunization with D-MAP B1-C failed to affect the challenge worm parameters, probably because peptides B1 and C, previously shown to elicit immune responses associated with increase and decrease in challenge worm fertility, respectively, induced immune responses with opposing effects when combined in a D-MAP construct. A similar suggestion may explain the failure of D-MAP D-E to protect the host against challenge infection. In contrast, immunization with D-MAP B-E resulted in robust protection of the host, possibly because it contains peptides known to evoke immune responses associated with a significant decrease in challenge worm burden and fertility. The data together suggest that the specificity, not the quantity, of the induced immune responses is the determining factor for the efficacy of synthetic peptide-based vaccine for schistosomiasis.