Abstract Background Agriculture workers are exposed to microbial component- and particulate matter-enriched organic dust aerosols. Whereas it is clear that exposure to these aerosols can lead to lung inflammation, it is not known how inflammatory responses are resolved in some individuals while others develop chronic lung disease. Interleukin (IL)-10 is an immunomodulatory cytokine that is recognized as a potent anti-inflammatory and pro-resolving factor. The objective of this study was to determine whether there is a relationship of systemic IL-10 and proinflammatory responses and/or respiratory health effects in humans with prior agriculture exposure. Methods This is a cross sectional study of 625 veterans with > 2 years of farming experience. Whole blood was stimulated with or without organic dust and measured for IL-6, TNFα and IL-10. Participants underwent spirometry and respiratory symptoms were assessed by questionnaire. Results We found that baseline IL-10 concentration from the whole blood assay was inversely associated with ΔTNF-α (r = − 0.63) and ΔIL-6 (r = − 0.37) levels. Results remained highly significant in the linear regression model after adjusting for age, sex, BMI, race, education, smoking status, and white blood cell count (ΔTNF-α, p