Abstract Objective To study the role of α 1 AT and TIMP-1 gene polymorphisms in development of COPD. Design and methods Blood samples from total 408 subjects (217 COPD patients and 191 controls) were used for genotyping and estimating biolevels of α 1AT, TIMP-1 and inflammatory cytokines. Data was analyzed to determine the role of interaction of TIMP-1 and α 1 AT genes; and interplay between various genotypes and biolevels of α 1AT, TIMP-1 and inflammatory cytokines in development of COPD. Results Significantly low levels of α 1AT and TIMP-1 were observed in COPD patients as compared to controls (P = 0.001), where as the inflammatory cytokines were found to be increased in patients. PIM3 allele of α 1 AT gene in COPD patients was found to be associated with low levels of α 1AT (P = 0.001), the effect being more pronounced when PIM3 combined with rs6609533 of TIMP-1 gene (P = 0.0001). Combination of genotypes rs6609533 of TIMP-1 and PIM3 of α 1 AT containing the risk alleles was over-represented in patients (P = 0.005). Conclusion The SNP rs6609533 of TIMP-1 gene interacted with PIM3 of α 1 AT to make a possible risk combination for development of COPD.