ObjectivesThis 2-part randomized parallel triple-blind clinical trial adopts a unique model assessing clinically-set hydraulic calcium silicate-based sealers (HCSBS) after different root canal dryness protocols and obturation techniques.MethodsFor the first phase of the study, 24 teeth scheduled for orthodontic extractions were allocated into four groups according to the canal dryness protocol and the obturation technique. G1 (CLC-AHP): cold lateral compaction (CLC) with AH Plus sealer, G2 (CLC-ES-SD): CLC with Endosequence (ES) after standard canal(s) dryness (SD); G3 (SC-ES-SD): matching single-cone (SC) with ES after SD; G4 (SC-ES-PD): as G3 but after partial canal(s) dryness (PD). Teeth were extracted after one month of clinical service and examined for intracanal voids by micro-CT (2D & 3D). For the 2nd phase, another 24 teeth were allocated into four groups according to the root canal dryness protocol and the HCSBS used (ES or CeraSeal (CeS)). Teeth were extracted after one month and sectioned vertically for energy dispersive X-ray (EDX)/scanning electron microscope (SEM) examination. One-way ANOVA with Games-Howell post-hoc test and Chi-square test with multiple z-tests were used for statistical analysis.ResultsSC-PD showed the highest percentage of voids (p < 0.05). MicroCT scans as well as EDX/SEM examination showed that PD resulted in significantly larger interfacial gaps (p < 0.001) with more hydration products at the sealer/dentin interface than SD.ConclusionsBoth tested dryness protocols allowed the hydration of HCSBS and the formation of hydration products, thus standard dryness is recommended to reduce the incidence of intracanal voids.Clinical relevanceWhen using the single-cone obturation technique, intentional root canal moisture negatively affects the performance of HCSBS.Protocol Registrationhttp://www.clinicaltrials.gov, ID: NCT05808062.