Objective: To evaluate and compare the effect of two different drying agents (PrimaDry and Ethyl alcohol 95% concentration.) on microleakage of filled (Ultraseal XT plus) and unfilled (Helioseal) fissure sealants in vivo and in vitro. Methods: A total of 60 extracted human upper and lower first premolars from (15) adult healthy patients were divided into 2 groups (30) in vitro and (30) in vivo (Teeth of this group were extracted 3 months after sealant application), each group were subdivided into 2 subgroups(15) sealed with filled (Ultraseal XT plus), while the other (15) were sealed with unfilled (Helioseal), each subgroup was subdivided into 3 classes composed of (5) premolars according to drying agent used: B0) without drying agent. B1)PrimaDry B2)Ethyl alcohol 95% concentration. Teeth were thoroughly washed with water, cleaned with non fluoridated (FL) prophylaxis paste. The unsealed were sealed outside the mouth (in vitro). The occlusal surfaces were opened using tapered diamond fissure burs confined to enamel. Fissure sealant application was done following the manufacturer's instructions. The drying agent was applied after etching and before sealant application. Dye penetration method using methylene blue dye for microleakage assessment. Teeth were coated from root apecies with melted utility wax leaving the sealant and approximately 2mm enamel around it uncovered. The wax was covered with a thin layer of tin foil then with 2 layers of nail varnishthen allowed to dry, and then the specimens were immersed in 1% methylene blue for 24h in order to allow dye penetration into possible gaps in the tooth–sealant interface. The coatings were then stripped off, the teeth rinsed thoroughly under running tap water, then sectioned longtudinally in buccolingual direction into two halves and two sections were obtained from each tooth using diamond saw, each section cleaned, examined and photographed under stereomicroscope at ×20 magnifications to assess dye penetration at the margins of the restorations. Two-way ANOVA was used for statistical analysis. Results: in vivo results revealed that unfilled (Helioseal) 2