Background: Cross-linked polyethylene was developed to reduce volumetric wear in prosthetic joints. Hip simulator studies have shown promising results with regard to wear reduction. This study evaluated the short-term in vivo wear of a moderately cross-linked polyethylene. Methods: Linear head penetration, as an assessment of in vivo polyethylene wear, was measured in two groups of patients after total hip replacement. Twenty-four hips received a conventional polyethylene insert and thirty-four, a crosslinked polyethylene liner; both inserts were manufactured by the same company. Linear and volumetric wear rates were measured on radiographs with use of a validated computer-assisted technique and were adjusted for patient-related factors. Patient activity was assessed by a computerized two-dimensional accelerometer worn on the ankle. Results: Patients with a conventional polyethylene insert showed a mean linear wear rate of 0.13 mm per year and a mean volumetric wear rate of 87.6 mm(3) per year. The group with a cross-linked polyethylene liner showed a mean linear wear rate of 0.02 mm per year and a mean volumetric wear rate of 17.0 mm(3) per year. Wear in the group with cross-linked polyethylene was 81% lower than that in the group with conventional polyethylene (p < 0.00001). Accounting for differences in patient activity, the adjusted wear rates per million cycles for a patient weight of 70 kg were 53 mm(3) per million cycles for conventional polyethylene and 15 mm(3) per million cycles for cross-linked polyethylene, a 72% reduction (p = 0.0002). No factor, other than the type of polyethylene, was found to influence the difference in wear rates between the two groups. Conclusions: The results of this study are promising. The in vivo wear reduction with this cross-linked polyethylene is consistent with the predictions of hip simulator studies. Level of Evidence: Therapeutic study, Level II-1 (prospective cohort study). See Instructions to Authors for a complete description of levels of evidence.