Background: Rare cardiovascular events of commonly used drugs are important to document and investigate, but single trials are notoriously underpowered to provide conclusive evidence. Recently, meta-analyses have been used to improve on the power. A recent rosiglitazone meta-analysis heightened the debate about the usefulness and limitations of meta-analysis in this setting. In this review, we examined the methods used in previous published meta-analyses for harmful cardiovascular events, with special attention to the rosiglitazone meta-analyses, and give suggestions for the improvement of methods and interpretation of such meta-analyses. The conduct of meta-analysis in this context is particularly difficult and requires timely investigation, availability of high-quality data on harms, and statistical expertise. There are important decisions that need to be made about selecting the appropriate analytical methods and performing sensitivity analyses to evaluate whether the results are robust to different analytical choices. © 2008 Mosby, Inc. All rights reserved.