Objectives The previously observed inverse association between hog farming and risk of lung cancer in the Agricultural Health Study (AHS) has been attributed to endotoxin exposure, the levels of which are particularly high in industrial hog confinement facilities. We conducted an investigation to explore the potential biological mechanisms underlying this association, as well as other immunological changes associated with hog farming. Methods Serum immune marker levels were measured using a multiplexed bead-based assay in 61 active hog farmers and 61 controls matched on age, phlebotomy date and raising cattle. Both groups comprised non-smoking male AHS participants from Iowa. We compared natural log-transformed marker levels between hog farmers and controls using multivariate linear regression models. Results Circulating levels of macrophage-derived chemokine (CCL22), a chemokine previously implicated in lung carcinogenesis, were reduced among hog farmers (17% decrease; 95% CI –28% to –4%), in particular for those with the largest operations (〉6000 hogs: 26% decrease; 95% CI –39% to –10%; p trend =0.002). We also found that hog farmers had elevated levels of other immune markers, including macrophage inflammatory protein-3 alpha (MIP-3A/CCL20; 111% increase, 95% CI 19% to 273%), basic fibroblast growth factor (FGF-2; 93% increase, 95% CI 10% to 240%) and soluble interleukin-4 receptor (12% increase, 95% CI 1% to 25%), with particularly strong associations for MIP-3A/CCL20 and FGF-2 in winter. Conclusions These results provide insights into potential immunomodulatory mechanisms through which endotoxin or other exposures associated with hog farming may influence lung cancer risk, and warrant further investigation with more detailed bioaerosol exposure assessment.