Background Several studies conducted in Europe have suggested a protective association between early-life farming exposure and childhood eczema or atopic dermatitis; however, few studies have examined associations in adults. Objectives We investigated associations between early-life exposures and eczema among 3217 adult farmers and farm spouses (mean age, 62.8 years) in a case–control study nested within an US agricultural cohort. Methods We used sampling-weighted logistic regression to estimate odds ratios and 95% confidence intervals for associations between early-life exposures and self-reported doctor-diagnosed eczema (273 cases) and polytomous logistic regression to estimate odds ratios (95% confidence intervals) for a 4-level outcome combining information on eczema and atopy (specific IgE ≥ 0.35). Additionally, we explored genetic and gene–environment associations with eczema. Results Although early-life farming exposures were not associated with eczema overall, several early-life exposures were associated with a reduced risk of having both eczema and atopy. Notably, results suggest stronger protective associations among individuals with both eczema and atopy than among those with either alone. For example, odds ratios (95% confidence intervals) for having a mother who did farm work while pregnant were 1.01 (0.60, 1.69) for eczema alone and 0.80 (0.65, 0.99) for atopy alone, but 0.54 (0.33, 0.80) for having both. A genetic risk score based on previously identified atopic dermatitis variants was strongly positively associated with eczema, and interaction testing suggested protective effects of several early-life farming exposures only in individuals at lower genetic risk. Conclusions In utero and childhood farming exposures are associated with decreased odds of having eczema with atopy in adults