A cohort of patients underwent prospective follow-up to delineate the natural history of screw-associated osteolysis in cementless Anatomic Modular Knee arthroplasty. In 1993, fluoroscopically guided radiographs were obtained in 230 patients (280 arthroplasties) to identify occult osteolysis. This cohort was reassessed periodically to identify new or progressive screw-associated osteolysis. At early follow-up, 94 knees (34%) had osteolysis. Osteolysis progressed in all groups, and osteolysis developed in 60 additional knees. At intermediate follow-up, 55% of knees showed radiographic evidence of osteolysis. Osteolysis progressed to a higher grade in a significant percentage of patients, and 23% of arthroplasties were revised. Regular periodic radiographic evaluation is recommended for early recognition of osteolysis.