There is growing evidence that the microvessels of the lung are involved in the pathobiology of emphysema and that the expression of vascular endothelial growth factor (VEGF), which has a vascular protective role, is decreased in the pulmonary arteries of patients with severe emphysema. The vascular protective effects of VEGF can be mediated through endothelial cell production of nitric oxide and prostacyclin (prostaglandin [PG] I2). PGI2 production in the lungs of patients with emphysema could be reduced as a consequence of reduced VEGF expression and/or other mechanisms. We wondered whether the expression of the gene encoding the critical enzyme PGI2 synthase (PGIS) was reduced in human emphysema lungs. We postulate that the decreased production of PGI2 is associated with the pulmonary vascular dysfunction observed in patients with emphysema. 6-keto-PGF1α, the stable metabolite of PGI2, was measured by enzyme-linked immunosorbent assay in whole-lung tissue extracts. The expression of PGIS protein was measured by Western blotting in whole-lung tissue extracts and was assessed by immunohistochemistry of paraffin-embedded tissues. The messenger RNA expression of PGIS was measured by real-time reverse transcriptase polymerase chain reaction. 6-keto-PGF1α levels were significantly decreased in patients with emphysema. The main site of decreased expression by immunohistochemistry were small pulmonary arteries. The expression of PGIS protein measured by Western blotting was decreased in patients with emphysema compared to that in healthy lungs. The messenger RNA expression of PGIS was also decreased in the lungs of patients with emphysema. Decreased PGIS expression may contribute to pulmonary vascular dysfunction in patients with emphysema and may also signal a premalignant condition. The molecular mechanism by which PGIS messenger RNA expression is down-regulated in patients with emphysema needs further evaluation.