Varespladib methyl is an oral secretory phospholipase A2 inhibitor that is being developed by Anthera Pharmaceuticals Inc for the potential treatment of coronary artery disease, acute coronary syndrome and inflammation. Varespladib methyl is a prodrug that is rapidly metabolized to varespladib, and both compounds are able to potently inhibit the enzymes of the human secretory phospholipase groups IIa, V and X, which play a pivotal role in atherosclerotic disease and inflammation. Phase II clinical trials of varespladib methyl in patients with coronary artery disease, rheumatoid arthritis, asthma and ulcerative colitis revealed that the drug was well tolerated. Varespladib methyl did not demonstrate a good efficacy profile in patients with rheumatoid arthritis, asthma and ulcerative colitis, whereas in patients with coronary artery disease, varespladib methyl consistently reduced LDL-cholesterol levels (elevated LDL-cholesterol levels are a marker of increased cardiovascular risk). At the time of publication, phase II trials were ongoing in patients with acute coronary syndrome and in patients undergoing elective percutaneous coronary intervention, and a phase III trial in patients with acute coronary syndrome was planned. Varespladib methyl could represent a novel therapy for the treatment of cardiovascular disease, although the efficacy, safety profile and advantages of this drug compared with existing therapeutic options would need to be established in upcoming phase III trials.