Background: Cardiovascular Diseases (CVD) are considered an overwhelming health burden in Saudi Arabia, greatly aggravated with the increasing rates of Diabetes Mellitus (DM) and obesity. Osteoprotegerin (OPG) is one of the tumor necrosis factor receptors, commonly associated with coronary heart diseases. This study examines the possible correlation among OPG with both DM and CVD. Methods: The study was conducted in Jeddah, Saudi Arabia and included 201 subjects. They were divided into four matched groups: group 1 were patients with CVD only; group 2 were patients with DM type 2; group 3 were patients suffering from DM and CVD, and group 4 was normal control. All groups were divided into male and female subgroups. The following parameters were measured; complete blood picture, lipid profile, insulin, fasting glucose and kidney function and also then relationship to OPG levels. Results: OPG was significantly elevated in males with CVD alone (8.31 ± 4.01 ng/ml), or in association with DM (6.54 ± 3.55 ng/ml). An increase was noted in female patients, but only in the DM and CVD groups (6.75 ± 3.3 ng/ml). A weak positive correlation was detected between OPG concentrations with both fibrinogen and glucose levels in females, while in males OPG levels were positively correlated with waist to hip ratios. Conclusion: OPG could be a valuable biomarker for early CVD appearance.