Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive fibrotic lung disorder of unknown etiology and unclear pathogenesis. Matrix metalloproteinase-1 (MMP-1) is strongly upregulated and may contribute to the abnormal remodeling that characterizes the disease. We conducted a case-control study of 130 IPF patients and 305 healthy controls to investigate associations between two polymorphisms of the MMP-1 gene promoter and IPF risk. First, using PCR-restriction fragment length polymorphism (PCR-RFLP) analysis we studied the 2G polymorphism at -1,607, shown previously to generate the core of an AP-1 binding site and correlate with high transcriptional activity and risk for IPF. The frequency of the 2G/2G genotype was higher in IPF than in controls (63 vs. 49%; P < 0.008; OR = 1.7; CI 1.15-2.79). Next, we studied a T/G SNP at position -755, which we identified by sequencing the MMP-1 promoter. Chromatin immunoprecipitation (ChIP) assay performed on IPF fibroblasts with either -755 genotype revealed an AP-1 binding site for TT(-755) and GT(-755) genotypes. The frequency of this SNP revealed no significant differences between IPF and healthy controls. However, when the study individuals were stratified by their smoking status, a significant increase in the T/T genotype frequency was observed in smoking cases compared with smoking controls (45 vs. 26%; P = 0.03; OR = 2.3; CI 1.15-4.97). These findings indicate that polymorphisms of the MMP-1 promoter may confer increased risk for IPF and reveal a putative gene-environment interaction between the -755 MMP-1 polymorphism and smoking in this disease.