Nicotinic acid (at a daily dose of grams) has been shown to induce potent anti-atherosclerotic effects in human and animal models. Evidence from clinical studies performed in the 1950s has shown that nicotinic acid treatment remarkably improves the plasma lipid profile. Large clinical studies showed that nicotinic acid improves clinical cardiovascular outcomes. Given the protective effects of niacin, basic research studies were designed to explore additional anti-atherosclerotic pathways, such as those involved in cardiovascular inflammation. After the discovery of the nicotinic acid receptor GPR109A on adipocytes and immune cells, novel direct immunomodulatory properties of nicotinic acid have been identified. Importantly, the regulation of the release of inflammatory mediators from adipose tissue was observed, independent of lipid level amelioration. Less is known about the possible direct anti-inflammatory activities of nicotinic acid in other cells (such as hepatocytes, endothelial and vascular cells) previously indicated as key players in atherogenesis. Thus, further studies are needed to clarify this promising topic. Emerging evidence from clinical and basic research studies indicates that novel direct anti-atherosclerotic properties might mediate nicotinic acid-induced cardiovascular protection. Despite some limitations in its clinical use (mainly due to the incidence of adverse events, such as cutaneous flushing and hepatotoxicity), nicotinic acid should be considered as a very potent therapeutic approach to reduce atherosclerosis. Promising research developments are warranted in the near future.