Chronic lung hypoxia causes vascular remodeling with pulmonary artery smooth muscle cell (SMC_PA) hyperplasia, resulting in pulmonary hypertension and cor pulmonale. We investigated SMC_PA and pulmonary artery adventitial fibroblasts (FB_PA) for their proliferative response to hypoxia. Strong SMC_PA growth occurred under hypoxic conditions in SMC_PA/FB_PA co‐cultures, but not in SMC_PA monocultures. SMC_PA growth was fully reproduced by transferring serum‐free supernatant from hypoxic cultured FB_PA to normoxic SMC_PA. Hypoxia‐inducible‐transcriptionfactor subtypes (HIF‐1α, HIF‐2α, HIF‐3α) and its dependent target genes, carrying the hypoxiaresponsive‐element as regulatory component, were strongly activated in both hypoxic FB_PA and SMC_PA. HIF‐transcription‐factor decoy technique, employed to FB_PA during hypoxic culturing, blocked the mitogenic activity of FB_PA conditioned medium on SMC_PA. The data suggest that hypoxia‐driven gene regulation in pulmonary artery fibroblasts results in a mitogenic stimulus on adjacent pulmonary artery smooth muscle cells, and HIF‐transcription‐decoy may offer a new therapeutic approach to suppress these events.