It is necessary apical plug material to exhibit proper adaptation with the root canal walls. Presence of voids at the interface between the root canal wall and this material result in micro leakage, which might have a relationship with post treatment disease. The aim of the present study was to evaluate the effect of different mixing (manual and ultrasonic) and placement (manual and manual in association with indirect ultrasonic) method of Mineral Trioxide Aggregate (MTA) on the void count and dimension in the apical plug in natural teeth with simulated open apices. Eighty human maxillary central incisors were selected. After simulation of the open apex model, the teeth were assigned to 4 groups based on the mixing and placement techniques of MTA: group 1, manual mixing and manual placement; group 2, manual mixing and manual placement in association with indirect ultrasonic; group 3, ultrasonic mixing and and manual placement; and group 4, ultrasonic mixing and manual placement in association with indirect ultrasonic. The prepared samples were placed within gypsum sockets in which the periodontal ligament was reconstructed with polyether impression material. In group 1, after mixing, the material was condensed with a hand plugger. In group 2, after mixing, the ultrasonic tip was contacted with the hand plugger for 2 seconds. In groups 3 and 4, mixing was carried out with the ultrasonic tip for 5 seconds and in groups 3 and 4, similar to groups 1 and 2, respectively, the materials were placed as apical plugs, measuring 3 mm in length. A wet cotton pellet was placed at canal orifices and dressed with Cavit. After one week, the cone beam computed tomography (CBCT) technique was used to count the number of voids between the material and root canal walls. The void dimensions were determined using the following scoring system: score 1, absence of voids; score 2, the void size less than half of the dimensions of the evaluated cross-section; score 3, the void size larger than half of the dimensions of the evaluated cross-section. Chi-squared and Fisher?s exact tests were used for statistical analyses. Statistical significance was set at P<0.05. The maximum (13) and minimum (3) number of voids were detected in groups 2 and 3, respectively. There were no significant differences between groups 1 and 3 in the number of voids (p >0.05). Evaluation of void dimensions showed no score 3 in any of the study groups and the dimensions of all the voids conformed to score 2. Under the limitations of the present study, use of ultrasonic mixing and manual placement techniques resulted in a decrease in the number of voids in the apical plug.