Imprinted genes often affect body size-related traits such as weight. However, the association of imprinting with obesity, especially childhood obesity, has not been well studied. Mexican-American children have a high prevalence, approaching 50%, of obesity and/or overweight. In a pilot study of 75 Mexican-American children, we analyzed the relationships among obese/overweight status, methylation status and single-nucleotide polymorphism (SNP) status at a CpG site in a differentially methylated region (DMR) of the imprinted H19/IGF2 locus. We observed a significant difference in SNP rs10732516 frequency between boys and girls among the overweight and obese children but not among the lean children. We also found that children with lower methylation of the polymorphic CpG site (CpG4) in the H19 DMR had higher birth weights than did children with higher methylation (P = 0.04). Our results suggest that CpG4 methylation status may be associated with childhood obesity in Mexican-American children in a sex-specific manner.