Background: Children with Down syndrome (DS) are at risk for autism spectrum disorder (ASD). They are often diagnosed later than other children in part due to difficulty differentiating ASD-related impairment from that associated with DS. The psychometric properties of the Pervasive Developmental Disorder in Mental Retardation Scale (PDD-MRS) were examined with the aim of informing ASD screening guidelines for children with DS. Method: Analysis of archival data from children aged 3 to 15 years with DS (N = 386) evaluated the reliability and validity of the PDD-MRS. Results: Factor analyses yielded 2 factor-based scales--"ASD" and "Emotional and Behavioural Problems." ASD reliably assessed ASD-specific symptoms, correlated with other ASD measures, and demonstrated good diagnostic accuracy. "Emotional and Behavioural Problems" assessed problems not diagnostic of ASD but may reflect part of the behavioural phenotype of DS and ASD. Conclusion: The PDD-MRS appears to have utility in ASD screening for this population.