Purpose: To characterize the prevalence of and contributing factors to adult obesity in the most common recurrent copy-number variation (CNV), 22q11.2 deletion, given that other rare CNVs are known to have obesity phenotypes. Methods: In 207 adults with 22q11.2 deletion syndrome (22q11.2DS), we used available height and weight measurements to calculate body mass index (BMI) and recorded associated factors that could play a role in obesity We used the maximum BMI per subject and logistic regression to test a model predicting obesity class. Results: The prevalence of obesity (BMI ?_30) in 22q11.2DS (n = 90,43.5%; at median age of 26.7 years) was significantly greater than for Canadian norms (odds ratio (OR) 2.30, 95% confidence interval (CI) = 1.74-3.02, P< 0.0001), even after exduding individuals with a history of antipsychotic use. The regression model was significant (P < 0.0001). Psychotropic medication use and age, but not sex or presence of intellectual disability, were associated with higher obesity level. Ten (4.8%) individuals were diagnosed with type 2 diabetes at, a median age of 39.5 years; the prevalence was higher in those with obesity (P < 0.01). Conclusion: The results suggest that adult obesity is related to the 22q11.2 deletion. The findings expand the potential genetic causes of obesity and have important implications for management of 22q11.2DS.