ABSTRACT: The purpose of this study was to compare the healing of pupal and periapical tissues in dogs after exposure to NeoMTA Plus and Quick-Set2 after pulpotomy and root-end surgery procedures. METHODOLOGY: Seventy-two teeth (36 for each procedure) in 6 beagle dogs received pulpotomy or root-end surgery using either NeoMTA Plus or Quick-Set2. The dogs were sacrificed at 90 days, and the teeth and surrounding tissues were prepared for histologic evaluation. Sixty teeth were evaluated and scored histologically (29 with pulpotomies and 31 with root-end resections). Specimens were scored for inflammation, quality and thickness of dentin bridging, pulp tissue response, cementum and periodontal ligament formation, and apical bone healing. RESULTS: Both materials displayed favorable healing at 90 days. The only significant difference was the quality of dentin bridge formation in pulpotomies using NeoMTA Plus compared with Quick-Set2. CONCLUSIONS: Quick-Set2 and NeoMTA Plus had similar effects on inflammation, pulp response, periodontal ligament and cementum formation, and apical tissue healing in dogs. NeoMTA Plus had superior dentin bridge quality compared with Quick-Set2.