Background: Maternal asthma and child's sex are among the most significant and reproducible risk factors for the development of asthma. Although the mechanisms for these effects are unknown, they likely involve nonclassical genetic mechanisms. One such mechanism could involve the transfer and persistence of maternal cells to her offspring, a common occurrence known as maternal microchimerism (MMc). MMc has been associated with many autoimmune diseases but has not been investigated for a role in asthma or allergic disease. Objective: We hypothesized that some of the observed risks for asthma may be due to different rates of transmission or persistence of maternal cells to children of mothers with asthma compared with children of mothers without asthma, or to sons compared with daughters.We further hypothesized that rates of MMc differ between children with and without asthma. Methods: We tested these hypotheses in 317 subjects from 3 independent cohorts by using a real-time quantitative PCR assay to detect a noninherited HLA allele in the child. Results: MMc was detected in 20.5% of the subjects (range 16.8%-27.1% in the 3 cohorts). We observed lower rates of asthma among MMc-positive subjects than among MMcnegative subjects (odds ratio, 0.38; 95% CI, 0.19-0.79; P =.029). Neither maternal asthma nor sex of the child was a significant predictor of MMc in the child (P =.81 and.15, respectively). Conclusions: Our results suggest for the first time that MMc may protect against the development of asthma.