The Child Behavior Checklist (CBCL) has been proposed for screening of autism spectrum disorders (ASD) in clinical settings. Given the already widespread use of the CBCL, this could have great implications for clinical practice. This study examined the utility of CBCL profiles in differentiating children with ASD from children with other clinical disorders. Participants were 226 children with ASD and 163 children with attention‐deficit/hyperactivity disorder, intellectual disability, language disorders, or emotional disorders, aged 2–13 years. Diagnosis was based on comprehensive clinical evaluation including well‐validated diagnostic instruments for ASD and cognitive testing. Discriminative validity of CBCL profiles proposed for ASD screening was examined with area under the curve (AUC) scores, sensitivity, and specificity. The CBCL profiles showed low discriminative accuracy for ASD (AUC 0.59–0.70). Meeting cutoffs proposed for ASD was associated with general emotional/behavioral problems (EBP; mood problems/aggressive behavior), both in children with and without ASD. Cutoff adjustment depending on EBP‐level was associated with improved discriminative accuracy for school‐age children. However, the rate of false positives remained high in children with clinical levels of EBP. The results indicate that use of the CBCL profiles for ASD‐specific screening would likely result in a large number of misclassifications. Although taking EBP‐level into account was associated with improved discriminative accuracy for ASD, acceptable specificity could only be achieved for school‐age children with below clinical levels of EBP. Further research should explore the potential of using the EBP adjustment strategy to improve the screening efficiency of other more ASD‐specific instruments. Autism Res 2015. © 2015 International Society for Autism Research, Wiley Periodicals, Inc.