Osseointegrated transfemoral amputation prostheses have proven successful as an alternative method to the conventional socket-type prostheses. The method improves prosthetic use and thus increases the demands imposed on the bone-implant system. The hypothesis of the present study was that the loads applied to the bone-anchored implant system of amputees would result in locations of high stress and strain transfer to the bone tissue and thus contribute to complications such as unfavourable bone remodeling and/or elevated inflammatory response and/or compromised sealing function at the tissue-abutment interface. In the study, site-specific loading measurements were made on amputees and used as input data in finite element analyses to predict the stress and strain distribution in the bone tissue. Furthermore, a tissue sample retrieved from a patient undergoing implant revision was characterized in order to evaluate the long-term tissue response around the abutment. Within the limit of the evaluated bone properties in the present experiments, it is concluded that the loads applied to the implant system may compromise the sealing function between the bone and the abutment, contributing to resorption of the bone in direct contact with the abutment at the most distal end. This was supported by observations in the retrieved clinical sample of bone resorption and the formation of a soft tissue lining along the abutment interface. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1113–1122, 2017.