Thiazolidinediones (TZDs) are synthetic peroxisome proliferator-activated receptor (PPAR) ligands that are widely used in type II diabetes treatment. In addition to their ability to improve glucose homeostasis, TZDs possess anti-inflammatory properties and inhibit growth of many cells, particularly cancerous airway epithelial cells. However, the functional effects of PPAR ligands on non-malignant human bronchial epithelial cells have never been investigated. In the present study, we questioned whether PPAR ligands may regulate proliferation of human bronchial epithelial cells and we studied their potential molecular mechanisms. We found that synthetic PPAR agonists, rosiglitazone (RGZ) and troglitazone (TGZ), induced proliferation of human bronchial epithelial cells whereas the endogenous PPAR ligand, 15-deoxy-^12,14-protaglandin J2 (15d-PGJ₂) inhibited cell growth. RGZ and TGZ (10µM) induced a rapid and transient intracellular calcium mobilization from thapsigargin-sensitive intracellular stores, whereas 15d-PGJ2 (5µM) did not induce any calcium signal. The PPAR antagonist, GW9662, did not inhibit any biological responses but it reversed the effect of 15d-PGJ₂ on cell growth. Using RT-PCR, we detected mRNA expression of the GPR40 receptor, a G protein-coupled receptor recently identified as a receptor for free fatty acids and TZDs, in human bronchial epithelial cells. Down regulation of GPR40 by small interfering RNA led to a significant inhibition of TZDs-induced calcium mobilization and proliferation. This study provides evidences for the proliferative effect of anti-diabetic drugs TZDs in non malignant human bronchial epithelial cells through GPR40 receptor activation, involving an intracellular calcium signaling pathway.