Several authors have demonstrated the safety and effectiveness of titanium in orbital reconstruction. One question posed by clinicians is what happens to large pieces of titanium in communication with the paranasal sinuses or nasal-oral-pharyngeal area. This question becomes increasingly relevant as titanium is used to reconstruct extensive defects for which the destruction of bony architecture requires the placement of mesh in proximity to these areas. The objective of this study was to examine the gross and histologic soft-tissue response to large segments of titanium mesh in the setting of orbital and midface reconstruction, particularly when exposed to the nasal-oral-pharyngeal area and paranasal sinuses. In this study, large segments of titanium mesh were used in eight patients to reconstruct orbital and midface defects, with direct communication between the mesh and nasal-oral-pharyngeal area and paranasal sinuses. Four patients had suffered self-inflicted gunshot wounds; as a result, much of their midface was missing, including the inferior and medial orbital floor, maxilla, nose, naso-orbital-ethmoid complex, and hard palate. Extensive sheets of titanium mesh were used to reconstruct their medial and inferior orbital walls, nasal bridge, and maxilla. In the fifth patient, titanium mesh was used to reconstruct the maxilla after resection of a squamous cell carcinoma of the nasolacrimal duct. In the sixth and seventh patients, mesh was used to reconstruct the nasal bridge after severely comminuted nasal fractures resulted in the loss of bone and mucosa. Finally, the eighth patient had titanium mesh used to replace cocaine-induced bone loss involving the left medial orbital floor and wall and part of the maxilla. On gross examination by either endoscopy or direct inspection, all eight patients had rapid soft-tissue incorporation of the titanium mesh. Initial examination typically revealed budding of soft tissue through mesh interstices, followed by progressive incorporation. One patient's mesh was covered in only 15 days. Two patients underwent biopsies of this newly formed soft tissue. One had biopsies performed at 3, 15, and 31 months after the original operation. Biopsy examination at 3 months revealed incorporation of the titanium with fibrous soft tissue covered by ciliated respiratory epithelium, goblet cells, and squamous epithelium with metaplasia. In addition, the dense, acute inflammation present at 3 months evolved into mild, chronic inflammation at 31 months. The second patient had a single biopsy 4 months after secondary orbital reconstruction for delayed enophthalmos. Biopsy examination revealed a fibrous soft-tissue sheath lined by squamous epithelium with metaplasia. Again, mild chronic inflammation was present within the soft tissue. This study provides evidence of titanium's compatibility with soft tissue. The mesh underwent progressive incorporation with soft tissue that was then resurfaced by indigenous cells, including respiratory epithelia and goblet cells. This phenomenon occurred despite communication with the nasal-oral-pharyngeal area and paranasal sinuses.