Cup orientation has been investigated in detail with respect to risk of dislocation, however, the impact on the primary fixation of cementless cups is poorly understood. The aim of this study was to assess the influence acetabular component orientation on the primary fixation of cementless acetabular cups using an in silico clinical trial framework. Finite element models of 57 implanted hemi-pelves were generated from CT scans of a cohort of end stage osteoarthritis patients. Each hemi-pelvis was implanted with the with cup orientations that bounded the Lewinnek safe zone (mechanical alignment +/−10 degrees) and an approximation of the extreme orientations reported in the literature (mechanical alignment +/−20 degrees). Bone strain immediately adjacent to the implant and micromotions (gap and shear micromotions) were used to assess primary fixation. Analysis was performed at the levels of the individual subjects and the entire cohort. There was minimal variation in all metrics within the Lewinnek safe zone. Micromotion, particularly inferior gaping, was more sensitive to cup orientation than peri-prosthetic bone strain, tending to increase with inclination angle. Both the peri-prosthetic bone strains and micromotions were moderately correlated to the average bone modulus. Individuals with low bone modulus were shown to be more sensitive to changes in cup orientation for both peri-prosthetic bone strains and micromotions both within and outside the Lewinnek safe zone. This suggests that assessing bone quality should be routinely incorporated into the planning process, particularly when considering cup orientations outside of the Lewinnek safe zone.