Velocardiofacial syndrome (VCFS) is a relatively common developmental neuropsychiatric syndrome caused by a 22q11 microdeletion. There is an extensive variability in the phenotypic expression of this disease. The most common psychiatric disorder in VCFS is attention-deficit/hyperactivity disorder (ADHD), affecting 35-55% of patients. This study investigated the association of familial, developmental, and physical factors with the occurrence of ADHD in 51 patients with nonfamilial VCFS. Twenty-one patients (41.2%) were diagnosed with ADHD. There was a significantly greater prevalence of ADHD in the first-degree relatives of the patients with ADHD than in those without (OR = 5.9, 95% CI = 1.6-22.1, P = 0.006). No differences were noted between the ADHD and non-ADHD groups in mean Obstetric Complication Scale Score, gestational age, birth weight, age at first words, walking, and achieving bowel control. The two groups also had similar IQ scores (total, verbal, and performance) and had a similar average degree of severity of facial dysmorphism and cardiac and cleft anomalies. These findings indicate that ADHD in VCFS has a genetic contribution and the patients' VCFS-related developmental factors and physical illnesses play a lesser role.