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Objectives To evaluate clinical, radiographic, microbiologic, and biomechanical parameters related to bone remodeling around implants with external hexagon (EH) and Morse-taper (MT) connections. Materials and Methods Twelve totally edentulous patients received four custom-made implants in the interforaminal region of the mandible. Two of those implants had the same macroscopic design, but different prosthetic connections. All patients received an immediate implant-supported prosthesis. Clinical parameters (periimplant probing pocket depth (PPD), modified gingival index (mGI), and mucosal thickness (MTh)) were evaluated at 12 months follow-up. The distance between the top of the implant and the first bone-to-implant contact (IT-FBIC) was evaluated on standardized digital peri-apical radiographs acquired at 1, 3, 6, and 12 months follow-up. Samples of the subgingival microbiota were collected 1, 3, and 6 months after implant loading and used for the quantification of Tanerella forsythia, Porphyromonas gingivalis, Aggragatibacter actinomycetemcomitans, Prevotella intermedia, and Fusobacterium nucleatum. Further, 36 computerized-tomography based finite element (FE) models were accomplished, simulating each patient under three loading conditions. Results The evaluated clinical parameters were equal for EH and MT implants. Mean IT-FBIC was significantly different between the tested connections (1.17 ± 0.44 mm for EH, and 0.17 ± 0.54 mm for MT, considering all evaluated time periods). No significant microbiological differences could be observed between tested connections. FE analysis showed a significantly higher peak of equivalent (EQV) strain (p = 0.005) for EH (mean 3,438.65 µe) compared to MT (mean 840.98 µe) connection. Conclusions Radiographic periimplant bone loss depends on the implant connection type. MT connections showed less periimplant bone loss, compared to EH connections.