The personality profile of 48 youngsters (24 males and 24 females, mean age 8 years, 5 months) with Velo-Cardio-Facial Syndrome (VCFS) was compared with a group of 240 non VCFS control youngsters (matched on age and gender), and, in addition, with groups of youngsters with Prader-Willi (PWS), Fragile X (FXS), and Williams Syndromes (WS). Personality characteristics of each youngster were rated by both parents, using the California Child Q-set (CCQ). The scores on eight personality dimensions were compared, i.e., Extraversion, Agreeableness, Conscientiousness, Emotional Stability, Openness, Motor Activity, Irritability, and Dependency. Moreover, Individual differences in personality of VCFS youngsters were related to IQ level, presence or absence of cardiac defects, and de novo versus familial origin of VCFS. The personality profile of VCFS youngsters was markedly different from all non-VCFS groups. Compared to the 240 control children, they were equally extravert and agreeable, less conscientious and emotional stable and more Irritable and dependent. Some personality characteristics in youngsters with VCFS were related to IQ and Age, but not to cardiac defects or de novo versus familial genetic origin of the 22q11 deletion.