Workers in swine operations are exposed to indoor dusts and gases and are at increased risk of respiratory problems. Toll-like receptor (TLR) 2 recognizes ligands from gram-positive bacteria, whereas TLR4 responds to endotoxin from gram-negative bacteria. To investigate the effects of TLR2 and TLR4 polymorphisms on lung function in workers from swine operations and nonfarming rural dwellers. A total of 374 full-time workers from large swine operations and 411 nonfarming rural dwellers from Saskatchewan were included. Information on demography, lifestyle, and occupation, lung function measurements, and blood samples for genotyping were obtained from the participants. Multiple regression analysis and Bonferroni correction were used in the statistical analysis. Workers with TLR2-16933T/A polymorphism (AA) had significantly greater mean values of lung function than workers with wild-type genotypes (AT+TT) after controlling for potential confounders (forced expiratory volume in 1 second, 3.7 vs 3.5 L; P=.009; forced expiratory flow between 25% and 75%, 3.7 vs 3.3 L; P=.003; predicted forced expiratory volume in 1 second; 100.3% vs 95.6%; P=.005; forced expiratory flow between 25% and 75%, 92.4% vs 83.4%; P=.009). These results were also observed for TLR2Arg677Trp polymorphism among the workers. No such significant differences were observed among nonfarming rural dwellers. For Asp299Gly and Thr399Ile polymorphisms in the TLR4 gene, no significant differences were observed in the mean lung function values between the polymorphic and wild-type groups in both workers and rural dwellers. Our study is the first, to our knowledge, to report protective effects of TLR2 polymorphisms on lung function among workers in swine operations and raises the possibility that TLR2 polymorphisms are protective of airway disease in individuals exposed to gram-positive organisms in the inhaled airborne dust.