Titanium-nitride-oxide coatings (TiNxOy) improve osseointegration of endosseous implants. The exact mechanisms by which these effects are mediated are poorly understood except for an increase of osteoblast proliferation while a high degree of differentiation is maintained. One hypothesis holds that TiNxOy facilitates the initial spreading and adhesion of the osteoblasts. The aim of this work was to investigate the molecular mechanisms of osteoblast adhesion on TiNxOy as compared to microrough titanium SLA. A global view of the osseointegrative process, that is, taking into account other cell groups, especially endothelial cells, is also presented. To this aim, gene expression and focal adhesion analysis, cocultures and wound assays were performed early after seeding, from 6 h to 3 days. We demonstrated that TiNxOy coatings enhance osteoblast adhesion and spreading when compared to the standard microrough titanium. The integrin β1, either in association with α1 or with α2 plays a central role in these mechanisms. TiNxOy coatings optimize the process of osseointegration by acting at several levels, especially by pregulating osteoblast adhesion and proliferation, but also by supporting neovascularization and the development of a suitable inflammatory environment.