Purpose: The current and projected shortage of transplantable human donor corneas has prompted the development of long-term alternatives to human donor tissue for corneal replacement. The biosynthetic stromal substitutes (BSS) characterized herein represent a potentially safe alternative to donor organ transplantation for anterior corneal stromal diseases. The goal of this phase 1 safety study was to characterize the three-dimensional (3D) corneal shape of the first 10 human patients implanted with a BSS and assess its stability over time. Methods: Ten patients underwent anterior lamellar keratoplasty using a biosynthetic corneal stromal implant for either advanced keratoconus or central corneal scarring. Surgeries were performed at Linköping University Hospital, between October and November 2007. Serial corneal topographies were performed on all eyes up to a 4-year follow-up when possible. Three-dimensional shape average maps were constructed for the 10 BSS corneas and for 10 healthy controls. Average 3D shape corneal elevation maps, difference maps, and statistics maps were generated. Results: The biosynthetic stromal substitutes implants remained stably integrated into the host corneas over the 4-year follow-up period, without signs of wound dehiscence or implant extrusion. The biosynthetic stromal substitutes corneas showed steeper surface curvatures and were more irregular than the healthy controls. Conclusions: Corneal astigmatism and surface steepness were observed 4 years after BSS implantation, while the implants remained stably integrated in the host corneas. Future studies will indicate if biomaterials technology will allow for the optimization of postoperative surface irregularity after anterior stromal replacement, a new window of opportunity that is not available with traditional corneal transplantation techniques.