Previous studies have shown that inherited taste blindness to bitter compounds like 6-n-propylthiouracil (PROP) may be a risk factor for obesity, but this literature has been highly controversial. The objectives of this study were (i) to confirm findings that show an interaction between PROP status and sex on BMI z-score, and (ii) to determine if sex also interacts with variations in TAS2R38 (phenylthiocarbamide (PTC) genotype) to influence weight status in 4-6 year olds. Also, we tested whether nontaster children consumed more fat and total energy at laboratory-based meals. Seventy-two ethnically diverse children who ranged in weight status were classified as tasters (N = 52) or nontasters (N = 20) using a standard PROP screening solution. Anthropometric measures were taken, and at the end of each visit, children ate ad libitum from test meals intended for exploratory purposes. Genomic DNA was extracted from saliva and alleles at TAS2R38 were genotyped for A49P polymorphisms. In 75.8% of children, PTC genotype predicted PROP phenotype, whereas in 24.4%, genotype did not predict phenotype. PROP nontaster males had higher BMI z-scores than taster-males and females in both groups (P < 0.05), but due to a three-way interaction between PROP phenotype, TAS2R38 genotype, and sex, this relationship was only true for children who were homozygous for the bitter-insensitive allele (P < 0.0005). There were no differences in test-meal intake as a function of PROP phenotype or TAS2R38 genotype. These results suggest that the TAS2R38 variation, PROP phenotype, and sex interact to impact obesity risk in children. Future studies should be done to determine how this trait influences energy balance.