Background: A variety of organic materials (biomass) are burned for cooking and heating purposes in poorly ventilated houses; smoke from biomass combustion is considered an environmental risk factor for chronic obstructive pulmonary disease COPD. In this study, we attempted to determine the participation of single-nucleotide variants in the HHIP (hedgehog-interacting protein) gene in lung function, HHIP serum levels, and HHIP sputum supernatant levels in Mexican women with and without COPD who were exposed to biomass-burning smoke. Methods: In a case-control study (COPD-BS, n = 186, BBES, n = 557) in Mexican women, three SNPs (rs13147758, rs1828591, and rs13118928) in the HHIP gene were analyzed by qPCR; serum and supernatant sputum protein levels were determined through ELISA. Results: The rs13118928 GG genotype is associated with decreased risk (p = 0.021, OR = 0.51, CI95% = 0.27–0.97) and the recessive genetic model (p = 0.0023); the rs1828591-rs13118928 GG haplotype is also associated with decreased risk (p = 0.04, OR = 0.65, CI95% 0.43–0.98). By the dominant model (rs13118928), the subjects with one or two copies of the minor allele (G) exhibited higher protein levels. Additionally, two correlations with the AG genotype were identified: BBES with FEV1 (p = 0.03, r2 = 0.53) and COPD-BS with FEV1/FVC (p = 0.012, r2 = 0.54). Conclusions: Single-nucleotide variants in the HHIP gene are associated with decreased COPD risk, higher HHIP serum levels, and better lung function in Mexican women exposed to biomass burning.