Bacterial nanocellulose (BNC) is a promising biomedical material. However, the haemocompatibility (haemolysis and thrombogenicity) and acute and sub-chronic immune responses to three-dimensional (3D) BNC biomaterials have not been evaluated. Accordingly, this manuscript focused on the effect of 3D microporosity on BNC haemocompatibility and a comparison with 2D BNC architecture, followed by the evaluation of the immune response to 3D BNC. Blood ex vivo studies indicated that compared with other 2D and 3D BNC architectures, never-dried 2D BNC presented antihemolytic and antithrombogenic effects. Nevertheless, in vivo studies indicated that 3D BNC did not interfere with wound haemostasis and elicited a mild acute inflammatory response, not a foreign body or chronic inflammatory response. Moreover, compared with the polyethylene controls, the implant design with micropores ca. 60 µm in diameter showed a high level of collagen, neovascularization and low fibrosis. Cell/tissue infiltration increased to 91% after 12 weeks and was characterized by fibroblastic, capillary and extracellular matrix infiltration. Accordingly, 3D BNC biomaterials can be considered a potential implantable biomaterial for soft tissue augmentation or replacement.