Background/Objectives: Luting agents are used to cement indirect restorations to teeth, and some of their components may induce pulpal reactions. This systematic review aims to evaluate the biocompatibility and effects of contemporary luting cements on the vital pulp. Methods: A comprehensive review of electronic databases PubMed, Cochrane Library, ScienceDirect, Web of Science, Scopus, and ClinicalTrials.gov was conducted for studies published between 2000 and 2026. Search strategies included MeSH terms, Boolean operators, and controlled vocabulary. Eligible studies included in vitro, ex vivo, in vivo, and clinical trials assessing pulpal responses to definitive luting cements in vital teeth or human-relevant pulp cell models. Screening and data extraction were performed independently by two reviewers. Risk of bias was assessed using the RoB 2 tool for clinical studies, QUIN for in vitro studies, SYRCLE for animal studies, and ROBINS-I for non-randomized human in vivo designs. Due to heterogeneity, meta-analysis was not performed, and a narrative synthesis was conducted. Results: From 1514 records, 40 studies met the inclusion criteria. Evidence was heterogeneous across study designs and outcomes. Human in vivo studies showed that short-term pulpal inflammation decreased over time, influenced by the remaining dentin thickness and material type. Clinical studies reported variable postoperative sensitivity. In vitro and ex vivo studies demonstrated material- and protocol-dependent effects on cell viability, oxidative stress, inflammatory markers, monomer release, and intrapulpal temperature rise. Conclusions: Luting cement selection should be case-dependent. Dual-cure, self-adhesive resin cements appear to demonstrate favorable biocompatibility in vital teeth; however, application protocols may influence cytotoxicity. Further clinically relevant studies are needed to support safer and biologically wise material selection. Registration: PROSPERO CRD420251156047.
Andreou et al. (Wed,) studied this question.