Background: Polybrominated diphenyl ethers (PBDEs) are persistent, bioaccumulative, and endocrine-disrupting chemicals. Objectives: We used handwipes to estimate exposure to PBDEs in house dust among toddlers and examined sex, age, breast-feeding, race, and parents' education as predictors of serum PBDEs. Methods: Eighty-three children from 12 to 36 months of age were enrolled in North Carolina between May 2009 and November 2010. Blood, handwipe, and house dust samples were collected and analyzed for PBDEs. A questionnaire was administered to collect demographic data. Results: PBDEs were detected in all serum samples (geometric mean for ΣpentaBDE in serum was 43.3 ng/g lipid), 98% of the handwipe samples, and 100% of the dust samples. Serum ΣpentaBDEs were significantly correlated with both handwipe and house dust ΣpentaBDE levels, but were more strongly associated with handwipe levels (r = 0.57; p < 0.001 vs. r = 0.35; p < 0.01). Multivariate model estimates revealed that handwipe levels, child's sex, child's age, and father's education accounted for 39% of the variation in serum ΣBDE₃ levels (sum of BDEs 47, 99, and 100). In contrast, age, handwipe levels, and breast-feeding duration explained 39% of the variation in serum BDE 153. Conclusions: Our study suggests that hand-to-mouth activity may be a significant source of exposure to PBDEs. Furthermore, age, socioeconomic status, and breast-feeding were significant predictors of exposure, but associations varied by congener. Specifically, serum ΣBDE₃ was inversely associated with socioeconomic status, whereas serum BDE-153 was positively associated with duration of breast-feeding and mother's education.