Selenium is an essential mineral that plays a crucial role in the regulation of cardiovascular system. The relation between selenium and cardiovascular disease (CVD) has been studied extensively over the last decades. In human prospective observational studies, there seems a U-shaped association between baseline selenium status and CVD risk, indicating possible adverse cardiometabolic effects of very low and high selenium levels. A few randomized controlled trials (RCTs) have evaluated the effects of selenium on CVD but showed no obvious benefits or risks. However, different population selenium status, selenium formulae, dosage, and intervention durations as well as trial quality may have contributed to between-trial heterogeneity, which largely prevents us from drawing causal conclusions. This chapter focuses on current evidence from prospective data, which helps to gain a more comprehensive insight into the selenium-CVD relationship and provide reasonable explanations of the discrepancies between results from human observational and interventional studies.