A total of seventy-six single canaled, recently extracted permanent human teeth were selected for the evaluation of the effect of different irrigation protocols on cleanliness and adhesion of epoxy-resin and glass-ionomer based sealers. The teeth were decapitated at CEJ, instrumented using K3 0.06 taper NiTi rotary system. They were divided into four main groups (each of 19 teeth) according to different irrigation protocols used during instrumentation:Group I: 1:1 mixture of 5.25% NaOCl + 18% Etidronic acid (HEBP). Group II: 1:1 mixture of 5.25% NaOCl + 18% Etidronic acid (HEBP), followed by 17% EDTA as a final rinse.Group III: 17% EDTA. Group IV: 5.25% NaOCl (control group). The quantity of irrigation was 5 ml for 2 minutes, each time during instrumentation. After complete instrumentation, a final rinse of 5 ml for 2 minutes of distilled water was done to remove any precipitates from irrigation regimens followed by paper points to dry and desiccate the canals. Sixteen roots of each group were chosen for obturation to evaluate the effect of different irrigation protocols on adhesion. They were subdivided into 2 subgroups (each of 8 roots), according to type of sealer used:1-A single gutta-percha cone size 40 taper 0.06 with AH Plus root canal sealer.2-A single Activ GP cone size 40 taper 0.06 with Activ GP root canal sealer. After 48 hours, the obturated roots were horizontally divided into three equal sections (cervical, middle, and apical). The middle third specimens were subject to push-out test by means of an Instron testing machine to examine the push-out bond strength. Then, the specimens were examined under digital microscope to determine the type of bond failure. The results were scored, tabulated, and subject to statistical analysis. The remaining three roots of each group having unobturated roots were chosen to evaluate of the effect of different irrigation protocols on cleanliness. They were longitudinally split into 2 equal halves. The walls of the middle thirds of their canals were examined for the presence of debris and smear layer under Environmental Scanning Electron Microscope (ESEM). The ESEM showed superior results of EDTA and NaOCl/HEBP/EDTA groups respectively in smear layer removal over NaOCl/HEBP and NaOCl groups. Dense smear layer in all specimens irrigated with NaOCl group was noticed and different variations from minimal to moderate smear layer in specimens irrigated with NaOCl/HEBP. The results of push-out test revealed that NaOCl/HEBP/EDTA treated groups recorded the highest mean value of bond strength, followed by EDTA treated groups, then NaOCl/HEBP treated groups. Meanwhile the lowest mean value was with NaOCl groups. Also, the push-out test revealed that Activ GP groups recorded higher mean value than that of AH Plus groups. Yet it was statistically insignificant. It was found that EDTA treated group recorded the highest mean value of push-out test with AH Plus sealer, while NaOCl/HEBP/EDTA treated group recorded the highest mean value of push-out test with Activ GP obturation system. Failure mode scores for AH Plus subgroups were predominately adhesive and mixed, while failure mode scores for Activ GP subgroups were predominately cohesive or mixed.