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AIM To develop an endodontic sealer with amoxicillin-loaded microsphere and to evaluate its properties. METHODS Experimental sealer was obtained by mixing 70wt% UDMA, 15wt% GDMA and 15wt% BISEMA. In addition, CQ, DHEPT and PB were incorporated at 1 mol% and 0.01wt% BHT and 10wt% YbF3. Microspheres were produced by drying in spray dryer. Two experimental groups (10 and 15wt% of microspheres) and one control group (without microspheres) were formulated. The sealers were evaluated for the degree of conversion (n=3), degradation in solvent (n=3), drug release profile (n=3), antimicrobial activity (n=3), flow (n=3), film thickness (n=3) and cytotoxicity (n=3). Data were analyzed by ANOVA and Tukey with significance level of 5%. RESULTS Microespheres presented a mean size of 2.664μm. Immediate degree of conversion ranged from 51.73% to 55.13% and the 24h degree of conversion ranged from 60.79% to 73.80%. Upon solvent degradation 54.44% and 56.21% reduction in hardness were observed for 10% and 15% concentrations respectivelly. The drug release profile showed an average release of 73.76% of the drug in 96h. Significant reduction in antimicrobial activity was observed for 10% concentration after 24h, 48h and 96h compared to control. The flow and film thickness showed values in accordance to the ISO 6876. Cytotoxicity showed high cellular viability. CONCLUSION The addition of up to 10% of microspheres containing amoxicillin presented antimicrobial activity and did not alter the properties of the experimental endodontic cement. CLINICAL SIGNIFICANCE Amoxicillin microspheres with its antimicrobial activity in root canal sealers could reduce reintervations in endodontics when persistent bacteria or reinfection takes place in root canal system.