Rationale: The majority of sarcoidosis patients resolve their condition, however 5-10% of subjects develop pulmonary fibrosis with poor prognosis. Prostaglandin-endoperoxide synthase 2 (PTGS2) is a key regulatory enzyme in the synthesis of the anti-fibrotic agent prostaglandin E₂ and is reduced in sarcoidosis lung. A promoter polymorphism -765G>C in PTGS2 is reported to reduce its expression. Objectives: To investigate if -765G>C associates with susceptibility to, and poorer outcome within, sarcoidosis and examine a possible mechanism by which -765G>C reduces PTGS2 expression. Methods: We used a case-control design study and genotyped -765G>C in a UK White British population of 198 sarcoidosis patients and 166 controls. Sarcoidosis patients were classified prior to genotyping as having persistent or non-persistent disease using clinical criteria which included chest radiography staging, need for treatment, lung function and longitudinal follow-up. Electrophoretic mobility shift assays (EMSA) were used to identify changes in transcription factor binding due to the -765G>C polymorphism. Results: Carriage of the -765C allele strongly associated with susceptibility to sarcoidosis (OR=2.50 [95%CI 1.51-4.13], P=0.006) and, within this disease, with poorer outcome (OR=3.11 [95%CI 1.35-7.13], P=0.008). The association with sarcoidosis was replicated in a second Austrian population. EMSAs revealed the -765C allele causes a loss of Sp1/Sp3 transcription factor binding and an increase in Egr-1 binding to the region. Conclusion: Our data suggests that the -765G>C polymorphism identifies individuals that are susceptible to sarcoidosis and, more importantly, at risk of pulmonary fibrotic disease. An altered Sp1/Sp3 binding to the -765 region may contribute to the mechanism by which -765G>C reduces PTGS2 expression.