The safety profile of pioglitazone has been evaluated in trials including over 5,400 subjects, of whom over 3,500 received active treatment resulting in over 2,500 patient-years of exposure. Since its launch, over 1.4 million patients have been prescribed pioglitazone. This paper will examine the clinical trial tolerability and safety data available for pioglitazone. Safety was evaluated both as monotherapy and in combination with other antihyperglycaemic drugs. All studies had a placebo-controlled, double-blind, randomised, parallel-group, multi-centre design, in which pioglitazone was administered once daily over a period of 16-24 weeks. Most trials also had a long-term open label extension. In these trials, adverse events were recorded, as were details of laboratory blood values, urine analysis, vital signs and electrocardiograms. In addition, specific studies were conducted to examine any effects of pioglitazone on cardiac structure and function, and body composition. This paper will also briefly review data available from post-marketing surveillance.