Purpose: This study was designed to evaluate and compare the effect of different cavity disinfectants on microleakage and interfacial micromorphology of class V resin composite restorations using two adhesive systems. Materials and Methods: Thirty six freshly extracted sound maxillary human premolar teeth were selected. Seventy two standardized class V cavities were prepared on both buccal and lingual surfaces of the selected premolars and randomly divided into three main groups (n=24) according to the cavity disinfectant used (A): silver nanoparticles (A1), ozone (A2), both of them (silver nanoparticles and ozone) (A3). Each group was subdivided into 2 subgroups (n=12) according to the type of the adhesive used (B): total-etch adhesive (B1), self-etch adhesive (B2). All cavities were restored with resin composite according to the manufacturer's instructions and subjected to thermocycling (500 cycles, 5oC -55oC). Ten cavities from each group were examined for microleakage. The interfacial micromorphology of the remaining 2 cavities was examined by environmental scanning electron microscope (ESEM). Data were expressed in scores. Results: There was a statistical significant difference between the different groups, where the highest leakage scores were found in the silver nanoparticles groups, followed by the combination groups (p ≤ 0.05). While the least leakage scores were found in the ozone groups. Also the highest leakage scores were more frequent in the self-etch groups as well as at the gingival margins of the restorations. Conclusions: Microleakage of class V resin composite restoration is affected by the type of cavity disinfectant; being improved by using ozone though deteriorated by using silver nanoparticles. It is better to use the total etch adhesive rather than the self-etch one.