Novel surface coatings of percutaneous implants need to be tested in biocompatibility studies. The use of animal models for testing usually involves numerous lethal biopsies for the analysis of the implant-tissue interface. In this study, optical coherence tomography (OCT) was used to monitor the reaction of the skin to a percutaneous implant in an animal model of hairless but immunocompetent mice. In vivo optical biopsies with OCT were taken at days 7 and 21 after implantation and post mortem on the day of noticeable inflammation. A Fourier-domain OCT was programmed for spoke pattern scanning schemes centered at the implant midpoint to reduce motion artifacts during in vivo imaging. Image segmentation allowed the automatic detection and morphometric analysis of the skin contour and the subcutaneous implant anchor. On the basis of the segmentation, the overall refractive index of the tissue within one OCT data set was estimated as a free parameter of a fitting algorithm, which corrects for the curved distortion of the planar implant base in the OCT images. OCT in combination with the spoke scanning scheme and image processing provided time-resolved three-dimensional optical biopsies around the implants to assess tissue morphology.