The phenotypic heterogeneity of adults suspected of autism spectrum disorder (ASD) requires a standardized diagnostic approach that is feasible in all clinical settings. The autism mental status exam (AMSE) is an eight-item observational assessment that structures the observation and documentation of social, communicative and behavioral signs and symptoms of ASD. Previous findings indicate high classification accuracy when compared to the autism diagnostic observation schedule in a non-stratified population of high-risk patients suspected of having ASD. This protocol investigates the sensitivity and specificity of AMSE scores using DSM-5 criteria for ASD in a sample of high-risk verbally fluent adults. Findings indicate an optimized sensitivity of 0.91 and a specificity of 0.93 for this group. Because of its high clinical utility, the AMSE holds promise as a diagnostic assessment tool that can support one's clinical diagnosis of ASD in high-risk adults.