We aimed to examine the effect of amoxicillin and azithromycin suspensions on the microhardness of sliver-reinforced glass ionomer and nano-resin modified glass ionomer (GI). Method: Thirty discs (2mm height x 4mm diameter) of each type of GI were prepared, which were randomly assigned to amoxicillin, azithromycin, and artificial saliva groups. Microhardness was evaluated by Vickers hardness test before and after three immersion cycles. Results: The overall model (P < 0.001), before/after intervention (P < 0.001), intervention group (type of antibiotic) (P=0.013), and type of glass ionomer (P < 0.001) showed significant differences among study groups (P < 0.001). Post hoc test showed only non-significant before/after difference for Azithromycin and artificial saliva (control) groups regarding nano resinmodified GI. Conclusion: We found significant microhardness loss for sliver reinforced GI in comparison to nano resin-modified GI after the immersion cycles. Yet, sliver reinforced GI would have higher level of microhardness than nano resin-modified GI after the immersion cycles. Longer time studies are required to assess trend of microhardness loss