Social skills impairment in children with Turner or fragile X syndrome has been documented using parental reports. Anxiety, shyness, and difficulty understanding social cues have been reported for females with Turner syndrome; whereas social withdrawal, avoidance of social interactions, and anxiety are often reported for females with fragile X syndrome. Social interaction anxiety in these two populations may be a framework for understanding the difficulty these children experience in social situations. In the present study, 29 females with Turner syndrome and 21 females with fragile X syndrome ages 6–22 years were compared to females in a comparison group, on a videotaped role-play interaction. Behavioral indices examined included eye-contact maintenance, duration of speech, and body discomfort as observed during the brief interaction. Three of eight such behavioral measures of social skills differentiated the participant groups from each other. Specifically, participants with fragile X required more time to initiate interactions than did participants in either of the remaining groups; and females with Turner syndrome made fewer facial movements than did females in the fragile X or comparison group. Self-report and parental ratings did not suggest higher levels of anxiety in females with Turner or fragile X syndrome, but did reflect higher levels of social difficulty. The authors discuss these findings in terms of understanding the nature of social dysfunction in females with Turner or fragile X syndrome.