The PROspective pioglitAzone Clinical Trial In macroVascular Events (PROactive) remains the only completed cardiovascular (CV) outcomes study with a thiazolidinedione. It has provided valuable information on the impact of pioglitazone on CV outcomes in a high-risk population of patients with type 2 diabetes and established macrovascular disease. The investigators in PROactive chose a challenging primary composite endpoint that included events in multiple vascular beds (cerebral, cardiac, and

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... ipheral), as well as both disease-related and procedural endpoints. They also pre-specified a more conventional main secondary composite endpoint of all-cause mortality, myocardial infarction, and stroke. Since the results of PROactive were first presented, there has been much debate on the relative merits of the statistically non-significant 10% decrease in the primary endpoint vs. the statistically significant 16% decrease in the main secondary endpoint seen with pioglitazone. However, PROactive includes more information than just these two main endpoints and has provided an extensive safety data set, as well as new insights into the impact of pioglitazone in different patient subpopulations. In this article, we consider all the results from PROactive presented to date and offer our own appraisal of how these findings shape the CV efficacy and safety profile of pioglitazone.