Background: Purpose of this study was to systematically examine combined use of the Autism Diagnostic Interview-Revised (ADI-R) and Autism Diagnostic Observation Schedule (ADOS) for children under age 4 using newly developed and revised diagnostic algorithms. Methods: Single and combined use of the ADI-R and ADOS algorithms were compared to clinical best estimate diagnoses for 435 children with autism spectrum disorders (ASD), 113 children with nonspectrum disorders, and 47 children with typical development from 12 to 47 months of age. Sequential strategies to reach a diagnostic decision by prioritizing administrations of instruments were also evaluated. Results: Well-balanced sensitivities and specificities above 80% were obtained for ASD diagnoses using both instruments. Specificities significantly improved when both instruments were used compared to one. Scores that can be used to systematically prioritize administrations of instruments were identified. Conclusions: The ADI-R and ADOS make independent, additive contributions to more accurate diagnostic decisions for clinicians evaluating toddlers and young preschoolers with ASD. Sequential assessment strategies using the scores identified may be appropriate for some children.