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 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 an HF diet. After 12 weeks on the diet, each mouse received a titanium implant in the proximal metaphysis of the femur. The animals were sacrificed at 4 or 8 weeks after the implant surgery. Results showed that the HF diet fed mice had significantly increased implant loss as well as decreased formation and strength of bone-to-implant interface. These results support the hypothesis that an HF diet can significantly compromise osseointegration, causing poor outcome in dental implant therapy.