The use of thiazolidinediones (TZDs) in the management of type 2 diabetes mellitus (T2DM) has been associated with an increased risk of peripheral edema. A meta-analysis was performed to assess the overall risk for developing edema secondary to TZD. A systematic literature search was conducted using five electronic databases. All prospective, randomized, either placebo-controlled or comparative studies reporting the incidence of edema with TZD therapy were included. Odds ratios were generated by pooling estimates across the studies. The analysis included 26 studies consisting of 15,332 patients with T2DM. The pooled odds ratio for TZD induced edema was 2.26 (95% CI: 2.02-2.53). The results yielded a higher risk for developing edema with rosiglitazone (3.75 [2.70-5.20]) compared to pioglitazone (2.42 [1.90-3.08]). Concordant results persisted with calculations of the adjusted indirect estimate. This meta-analysis demonstrates at least a two-fold increase in the risk for developing edema with a TZD agent. The risk appears to be greater with rosiglitazone than with pioglitazone. Further studies are needed to explore this difference.