Complementary clinical and laboratory studies were performed to identify variables associated with polyethylene wear following total hip replacement, and to elucidate the mechanisms responsible for accelerated wear in the total hip arthroplasty construct. Observational cohort studies were performed using a prospective clinical database of more than 4000 consecutive primary total hip arthroplasties performed by a single surgeon, to identify wear-related variables. These variables included head size, acetabular/femoral component impingement, and third body debris. Novel digital edge detection techniques were developed and employed to accurately measure wear, and to determine the relationships of head size and third body debris to acceleration of wear. A novel sliding-distance-coupled finite element model was formulated and employed to examine the mechanisms responsible for wear. The long-term cohort studies demonstrated smaller head sizes to be associated with less wear. Third body debris generated from cable fretting was associated with an increase in wear, osteolysis, and acetabular loosening, especially with larger head sizes. The sliding-distance-coupled finite element model replicated the wear rates occurring in vitro and in vivo, demonstrating the importance of sliding distance on polyethylene wear following total hip arthroplasty. It also demonstrated substantial increases in wear associated with femoral head scratching from third body debris. Further extension of the finite element formulation demonstrated the potential for acetabular component rim damage from impingement wear, and the enhanced potential for third body ingress to the bearing surface with larger head sizes. Edge detection wear measurement techniques demonstrated that early wear rates were predictive of long-term wear rates. These complementary clinical and laboratory investigations have provided insight into 1) the significance of sliding distance and physiologic loci of motion as contributing factors in minimizing wear, 2) the deleterious effects of third body particulates in accelerating wear, 3) the potential for, and factors related to, impingement wear, and 4) the potential advantages and compromises related to the use of larger head sizes in the bearing surface construct.