The most common chromosomal abnormalities associated with autism are 15q11-q13 duplications. Maternally derived or inherited duplications of 15q pose a substantial risk for an autism phenotype, while paternally derived duplications may be incompletely penetrant or result in other neurodevelopmental problems. Therefore, the determination of maternal versus paternal origin of this duplication is important for early intervention therapies and for appropriate genetic counseling to the families. We adapted a previous single-reaction tube assay (high-resolution melting curve analysis) to determine the parent of origin of 15q duplications in 28 interstitial duplication 15q samples, one family and two isodicentric subjects. Our method distinguished parent origin in 92% of the independent samples as well as in the familial inherited duplication and in the two isodicentric samples. This method accurately determines parental origin of the duplicated segment and measures the dosage of these alleles in the sample. In addition, it can be performed on samples where parental DNA is not available for microsatellite analysis. The development of this single-tube assay will make it easier for genetic testing laboratories to provide parent-of-origin information and will provide important information to clinical geneticists about autism risk in these individuals.