Root canal sealers with antimicrobial activity are highly beneficial; therefore, their antimicrobial properties could be improved by incorporation of antimicrobial agents. In the present study, the release of the quaternary ammonium compounds from endodontic sealers admixed with either benzalkonium chloride (BC) or cetylpyridinium chloride (CPC) at loadings of 2% wt was monitored. The effect of these additives on the compressive strengths and their release from the sealers was determined after 1 and 4 weeks. All of the materials studied were found to be capable of releasing antimicrobial additive in useful quantities. The release of CPC occurred to a statistically significant greater extent than BC for all materials. The addition of both BC and CPC generally decreased the compressive strength of all the endodontic sealers, with the exception of CPC in AH Plus, where the compressive strength was significantly increased. This suggests that, for these endodontic sealers, the antimicrobial additives alter the setting chemistry. AH Plus is an epoxy-based material cured with an amine, and in this case the increase in compressive strength with CPC is attributed to an enhanced cure reaction with this system. In all other cases, the additive inhibited the cure reaction to a greater or lesser extent.