This in vitro study evaluated the effect of an oxalate desensitizer (OX) on the marginal microleakage of resin composite restorations bonded by two three-step and two two-step etch and rinse adhesives. Class V cavities were prepared on the buccal surfaces of 126 extracted premolars at the cementoenamel junction and randomly divided into nine groups of 14 each. In the control groups (1-4), four adhesives were applied, respectively, including Adper Scotchbond Multi-Purpose (SBMP), Optibond FL (OBFL), One-Step Plus (OS) and Excite (EX). In the experimental groups (5-8), the same adhesives, in combination with OX (BisBlock), were applied. And, in one group, OX was applied without any adhesive, as the negative control group (9). All the groups were restored with a resin composite. After 24 hours of storage in distilled water and thermocycling, the samples were placed in 1% methylene blue dye solution. The dye penetration was evaluated using a stereomicroscope. The data were analyzed using non-parametric tests. The OX application, in combination with OBFL and EX, resulted in significantly increasing microleakage at the gingival margins (p < 0.05), while it had no effect on OS and SBMP (p > 0.05). At the occlusal margins, no significant difference in microleakage was observed after OX application for each of four adhesives (p > 0.05).