BackgroundDespite recognition of histoplasmosis as a disease of national public health concern in Kenya, the burden ofHistoplasma capsulatumin the general population remains unknown. This study examined the human seroprevalence of anti-Histoplasmaantibody and explored associations between seropositivity and demographic and environmental variables, in Busia county, western Kenya.MethodologyBiobanked serum samples and associated data, from a previous cross-sectional survey, were examined. Latex agglutination tests to detect the presence of anti-Histoplasmaantibody were performed on serum samples from 670 survey respondents, representing 178 households within 102 sub-locations.Potential epidemiologic risk factors forH.capsulatumexposure were explored using multi-level multivariable logistic regression analysis with household and sub-location included as random effects.Principal findingsThe apparent sample seroprevalence of anti-Histoplasmaantibody was 15.5% (n= 104/670, 95% Confidence Interval (CI) 12.9–18.5%). A multivariable logistic regression model identified increased odds ofH.capsulatumseropositivity in respondents reporting rats within the household within the previous 12 months (OR = 2.99 90% CI 1.04–8.55,p= 0.04). Compared to respondents aged 25–34 years, the odds of seropositivity were higher in respondents aged 15–24 years (OR = 2.70 90% CI 1.04–6.97,p= 0.04).ConclusionsThe seroprevalence result provides a baseline for sample size approximations for future epidemiologic studies of the burden ofH.capsulatumexposure in Busia county. The final model explored theoretically plausible risk factors forH.capsulatumexposure in the region. A number of factors may contribute to the complex epidemiological picture impactingH.capsulatumexposure status at the human-animal-environment interface in western Kenya. FocussedH.capsulatumresearch is warranted to determine the contextual significance of identified associations, and in representative sample populations.