BACKGROUND: We conducted a population-based human exposure study in response to concerns among the population of Midland and Saginaw counties, Michigan, that discharges by the Dow Chemical Company of dioxin-like compounds into the nearby river and air had led to an increase in residents' body burdens of polychlorinated dibenzofurans (PCDDs), polychlorinated dibenzofurans (PCDFs), and dioxin-like polychlorinated biphenyls (PCBs), here collectively referred to as “dioxins.” OBJECTIVES: We sought to identify factors that explained variation in serum dioxin concentrations among the residents of Midland and Saginaw counties. Exposures to dioxins in soil, river sediments, household dust, historic emissions, and contaminated fish and game were of primary interest. METHODS: We studied 946 people in four populations in the contaminated area and in a referent population, by interview and by collection of serum, household dust, and residential soil. Linear regression was used to identify factors associated with serum dioxins. RESULTS: Demographic factors explained a large proportion of variation in serum dioxin concentrations. Historic exposures before 1980, including living in the Midland/Saginaw area, hunting and fishing in the contaminated areas, and working at Dow, contributed to serum dioxin levels. Exposures since 1980 in Midland and Saginaw counties contributed little to serum dioxins. CONCLUSIONS: This study provides valuable insights into the relationships between serum dioxins and environmental factors, age, sex, body mass index, smoking, and breast-feeding. These factors together explain a substantial proportion of the variation in serum dioxin concentrations in the general population. Historic exposures to environmental contamination appeared to be of greater importance than recent exposures for dioxins.