The clinical relevance of numerical predictions of failure mechanisms in femoral prosthesis could be impaired due to simplification of musculoskeletal loading. This study investigated the extent to which loading configurations affect the preclinical analysis of an uncemented femoral implant. Patient‐specific, CT‐scan based FE models of intact and implanted femurs were developed and analysed using three loading configurations, which comprised of load cases representing daily activities. First loading configuration consisted of two load cases, each of walking and stair climbing. The second consisted of more number of load cases for each of these activities. The third included load cases of additional activities of standing up and sitting down. Failure criteria included maximum principal strains, interface debonding, implant‐bone relative displacement and adaptive bone remodelling. Simplified loading configurations led to a reduction (100‐1500 με) around cortical principal strains. The area prone to interface debonding were observed in the proximo‐medial part of implant and was maximum when all activities were considered. This area was reduced by 35%, when simplified loading configurations were chosen. Interfacial area of 88%‐96% experienced implant‐bone relative displacements below 40 μm; however maximum of 110 μm was observed at the calcar region. Lack of consideration of variety of activities overestimated (30%‐50%) bone resorption around the lateral part of the implant; hence, these bone remodelling results were less clinically relevant. Considering a variety daily activities along with an adequate number of load cases for each activity seemed necessary for pre‐clinical evaluations of reconstructed femur.