The purpose of this study was to investigate the pulpal response to direct pulp capping with dentin sialo-protein (DSP) -derived synthetic peptide in teeth of dogs, and to compare its efficacy to capping substances Ca(OH)₂ and white mineral trioxide aggregate (WMTA). A total of 72 teeth of 6 healthy male beagle dogs were used. The mechanically exposed pulps were capped with one of the following: (1) DSP-derived synthetic peptide (PEP group); (2) Ca(OH)₂ (CH group); (3) a mixture paste of peptide and Ca(OH)₂ (PEP+CH group); or (4) white MTA (WMTA group). The access cavity was restored with a reinforced glass ionomer cement. Two dogs were sacrificed at each pre-determined intervals (2 weeks, 1 month, and 3 months). After the specimens were prepared for standard histological processing, sections were stained with hematoxylin and eosin. Under a light microscope, inflammatory response and hard tissue formation were evaluated in a blind manner by 2 observers. In the PEP group, only 3 of 17 specimens showed hard tissue formation, indication that the DSP-derived synthetic peptide did not induce proper healing of the pulp. Compared with the CH group, the PEP group demonstrated an increased inflammatory response and poor hard tissue formation. The CH and WMTA groups showed similar results for direct pulp capping in mechanically exposed teeth of dogs.