People with type 2 diabetes mellitus have an excess risk of macrovascular disease and a poorer prognosis. PROactive (PROspective pioglitAzone Clinical Trial In macroVascular Events) was a landmark study of secondary cardiovascular disease (CVD) prevention in type 2 diabetes that suggested a beneficial effect of pioglitazone therapy on macrovascular outcomes. Previous studies have already shown that pioglitazone has a good safety and tolerability profile in people with type 2 diabetes, but PROactive provided an opportunity to assess tolerability and safety associated with long-term exposure in a vulnerable subpopulation at very high cardiovascular risk. This review discusses all the key safety and tolerability characteristics associated with pioglitazone therapy in PROactive. As in previous studies, pioglitazone was associated with typical, but manageable, increases in oedema (26.4% vs 15.1% for placebo) and weight gain (mean change of +3.8 kg vs -0.6 kg for placebo). Increased hypoglycaemia with pioglitazone was consistent with improved glycaemic control. Despite more reports of serious heart failure in the pioglitazone group (5.7% vs 4.1% for placebo), there was a proportional improvement in macrovascular outcomes among patients developing heart failure, and absolute rates of macrovascular events and mortality were similar to those in the placebo group. Liver function tests confirmed the hepatic safety of pioglitazone with long-term use and revealed a tendency to improved hepatic function, which may reflect reductions in liver fat. The comparative incidence of malignancies was similar; however, more cases of bladder neoplasm (14 vs 5) and fewer cases of breast cancer (3 vs 11) were observed in the pioglitazone versus placebo arms of the study. A higher rate of bone fractures observed among pioglitazone-treated female patients (5.1% vs 2.5%) warrants further investigation. Overall, safety and tolerability was predictable, and adverse events were not treatment limiting. These results suggest that any beneficial effects of pioglitazone on macrovascular outcomes are accompanied by good long-term tolerability in this population of very high-risk patients with type 2 diabetes and established CVD.