We describe two new site-specific ligation methods for preparing branched peptide dendrimers such as multiple antigen peptide (MAP). Both methods are based on the general approach of exploiting the specific reaction between a weak base and an aldehyde under acidic conditions so that unprotected peptides can be used as building blocks. A weak base such as benzoyl hydrazine or 1,2-amino thiol of cysteine was attached to the N-terminal of an unprotected peptide as nucleophile to react with the alkyl aldehyde on the core matrix of MAP to form a stable hydrazone linkage or a five-membered thiazolidine ring, respectively. Two synthetic peptides rich in basic amino acids such as lysine and arginine were used as models in the ligation reactions in solution to give peptide dendrimers containing four or eight copies of peptide immunogens. The resulting macromolecules with the MW ranging from 5 to 16 kDa were unambiguously characterized by laser-desorption mass spectrometry. Furthermore, we also optimized the conditions of these ligation reactions using elevated temperature and a water-miscible organic co-solvent to give a combination of rate enhancement about 10 fold. These optimizations allowed the ligation reactions to be completed in < 4 h instead of 2-3 days. Our ligation approach also has the advantages of flexibility so that peptides can be attached through the amino or carboxyl terminus to the core matrix. The phenyl hydrazone linkage and the five-membered ring were found to be stable at physiological pH suitable for immunization. Thus our results provide two practical and useful methods for the synthesis of macromolecular peptide dendrimers for vaccines, artificial proteins, and enzymes.