The composite of high density polyethylene reinforced with silane-modified TiO2 particles (silane-TiO2/HDPE) is a potential bone substitute biomaterial. The structure, bioactivity, and mechanical properties of silane-TiO2/HDPE are analogous to those of natural bone, correspondingly. In order to investigate the effect of silane connection and saline solution on fatigue behaviors, flexural fatigue tests with this composite were carried out in both air and saline solution. Saline solution was found to have different effect on fatigue life. In saline solution, the fatigue life could be improved at stress levels lower than 30 MPa, while the fatigue life could be reduced at stress levels higher than 30 MPa. After analyzing the fracture morphologies, different failure mechanisms were proposed, and the important role of silane connection in the composite during the fatigue process was discussed. Silane connection cannot only support the loading stress but also hinder the failure process under loading effectively. For dry specimens, no interfacial failure between the filler and matrix was found. For wet specimens, it is inferred that the synergetic effect of saline solution and high concentrated stress at high stress level could easily destroy the silane connection, which accelerated the fracture process, whereas the synergetic effect of saline solution and silane connection at low stress level could promote the formation of more microcracks on sample surface, which hindered the final fracture. The structure, bioactivity, and mechanical properties of silane-TiO2 / HDPE are analogous to those of natural bone, correspondingly In order to investigate the effect of silane connection and saline solution on fatigue behaviors, flexural fatigue tests with this composite were carried in both air and saline solution. After analyzing the fracture morphologies, different failure mechanisms were proposed, and the important role of silane connection in the composite during the fatigue process was discussed. Silane connection can not only support the loading stress but also hinder the failure process under loading effectively. For dry specimens, no interfacial failure between the filler and matrix was found. For wet specimens, it is inferred that the synergetic effect of saline solution and high concentrated stress at high stress level could easily destroy the silane connection, which accelerated the fracture process, while the synergetic effect of saline solution and silane connection at low stress level could promote the formation of more microcracks on the sample surface, which hindered the final fracture.