Introduction: Quick-Set (Primus Consulting, Bradenton, FL) is a calcium aluminosilicate cement that is a potential alternative to mineral trioxide aggregate (MTA) with greater acid resistance and faster setting. The purpose of this study was to compare the effects of Quick-Set and MTA on pulpal tissues in response to pulpotomy procedures. Methods: The pulp chambers of 42 maxillary teeth in 7 beagle dogs were accessed, and the coronal pulpal tissue was removed. Pulpotomy procedures were performed, placing the experimental materials directly over the radicular pulp tissues. The dogs were sacrificed at 70 days, and the teeth and surrounding tissues were removed and prepared for histologic analysis. The sections of the pulpotomy areas were scored for inflammation, pulp tissue organization, reactionary dentin formation, and quality of dentinogenesis. Results: The Quick-Set group exhibited significantly more pulpal inflammation (P = .002) and significantly less pulp tissue organization (P = .004). No significant difference was noted for reactionary dentin formation (P = .526) and quality of dentinogenesis (P = .436). Conclusions: Compared with ProRoot White MTA (Dentsply Tulsa Dental Specialties, Tulsa, OK), Quick-Set exhibited more pulpal inflammation and decreased pulp tissue organization. No significant differences were noted for reactionary dentin formation and quality of dentinogenesis. (J Endod 2015;-:1–5)