Introduction: Hydraulic silicate cements such as mineral trioxide aggregate (MTA) have many clinical advantages. Newer hydraulic silicate materials have been developed that improve on the limitations of mineral trioxide aggregate such as the long setting time and difficult handling characteristics. The purpose of this study was to examine the effect of saline and fetal bovine serum (FBS) on the setting and compressive strength of the following hydraulic silicate cements: Pro- Root MTA (white WMTA; Dentsply International, Tulsa Dental Specialties, Johnson City, TN), EndoSequence Root Repair Material (Brasseler USA, Savannah, GA), MTA Plus (MTAP; Avalon Biomed Inc, Bradenton, FL), and QuickSet (QS; Avalon Biomed Inc, Bradenton, FL). Methods: Samples of root-end filling materials were compacted into polyethylene molds. Samples were exposed to FBS or saline for 7 days. A universal testing machine was used to determine the compressive strengths. Results: QS had significantly lower compressive strength than all other materials (P < .001). White MTA and MTAP mixed with liquid had lower compressive strengths after exposure to FBS compared with saline (P = .003). ERRM, MTAP mixed with gel, and QS were not affected by the exposure to FBS. Conclusions: New silicate-based root-end filling materials, other than QS, have compressive strength similar to MTA. Within the limits of this study, premixed materials and those mixed with antiwashout gel maintain their compressive strength when exposed to biological fluids. (J Endod 2014;40:969–972).