Atherosclerosis plays a key role in cardiovascular disease in patients with rheumatoid arthritis (RA). Although therapy with TNF-alpha antagonists has resulted in dramatic improvement in the prognosis of RA, its effects on circulatory lipids are unclear. We conducted a systematic review of the literature to summarize the available evidence on lipid profile modification in patients with RA treated with TNF-alpha antagonists, with extensive searches in PubMed, the Cochrane Collaboration database (Central), and SCOPUS. Twenty-four observational studies met the inclusion criteria; 12 included only patients with RA treated with infliximab and three, patients with RA treated with adalimumab. The other nine included a mix of patients with various rheumatic diseases, or receiving one of several TNF-alpha antagonists. Eleven studies found a statistically significant increase in total cholesterol (TC) and high-density lipoprotein (HDL); six of 20 found significant increases in triglycerides (TG). Four of 13 studies found a statistical increase in low-density lipoprotein. No major changes were observed for ApoB/ApoA1 ratios. A small trend to increased TC was observed in patients receiving TNF-alpha antagonists, mostly due to an increase in HDL. There was a small trend to increased TG, and no changes in ApoB/ApoA1 ratio. The clinical impact of these findings is unclear, and further studies are needed to clarify the role of these lipid changes on cardiovascular morbidity in RA.