A high-fat (HF) diet inducing hyperlipidemia has been associated with the pathophysiology of major diseases, such as atherosclerosis and osteoporosis. A HF diet has significant adverse effects on bone, including lower bone density, volume, and strength. Statins, drugs that lower serum cholesterol levels have beneficial effects on bone metabolism. Since the host's bone quantity, quality, and healing potential play a crucial role in osseointegration of dental implants, we hypothesized that hyperlipidemia may negatively affect implant osseointegration. In the present study, we evaluated the effects of hyperlipidemia on implant osseointegration in mice. Atherosclerosis susceptible C57BL/6J male mice were randomly placed on a control chow or a HF diet. After 12 weeks on the diet, each mouse received a titanium implant in the proximal metaphysis of the femur. The animals were humanely killed at 4 or 8 weeks after the implant surgery. Results showed that the mice fed a HF diet had significantly increased implant loss as well as decreased formation and strength of bone-to-implant interface. These results support the hypothesis that a HF diet can significantly compromise osseointegration, causing poor outcome in dental implant therapy.