Background: Cardiac fibroblasts (CF) account for two-thirds of the total number of cells in the heart and are fundamental in the maintenance of its structural integrity. Thiazolidinediones (TZDs) are insulin sensitising agents used in the treatment of type 2 diabetes and are agonists for PPARγ (peroxisome proliferator activated receptor-γ). Previous studies suggest that TZDs may have beneficial effects on adverse cardiac remodelling, a key feature of which is increased CF migration, proliferation and secretion of matrix degrading metalloproteinases (MMPs). No previous studies have investigated the effects of TZDs on these aspects of human CF function. Aims: The aims of this project were two-fold. Firstly, to determine any functional effects of TZDs on human CF and secondly, to determine whether these effects occur via activation of PPARγ. Methods and Results: Human CF were cultured from right atrial appendage of patients undergoing coronary artery bypass surgery. TZDs (ciglitazone, rosiglitazone, troglitazone) and 15-deoxy-δ12,14-prostaglandin J2 (15d-PGJ2, endogenous ligand for PPARγ) inhibited CF proliferation in a concentration dependent manner, with similar efficacy. GW9662 and T0070907 (selective PPARγ antagonists) failed to reverse the inhibitory effects of TZDs on proliferation and unexpectedly had an inhibitory effect themselves. TZDs and 15d-PGJ2 had no marked effect on CF migration and invasion, as determined using modified Boyden chamber assays, in the absence or presence respectively, of a Matrigel basement membrane barrier. Gelatin zymography revealed that TZDs and 15d-PGJ2 did not inhibit IL-1α-induced MMP-9 secretion. Conclusion: TZDs clearly have pleiotropic effects and may have potential to attenuate adverse myocardial remodelling, by modulating CF proliferation, but not invasion or MMP-9 secretion. The anti-proliferative effects of TZDs occured independently of PPARγ activation. Since type 2 diabetic patients are at increased risk of coronary heart disease, treatment with TZDs may not only increase insulin sensitivity, but also have cardioprotective effects.