Adolescents and young adults with Down syndrome (DS) sometimes experience new-onset mood disorder and decline in adaptive skills. The clinical phenomenon is poorly characterized and its pathogenesis is not understood. The possible contribution of obstructive sleep apnea syndrome (OSAS) to this phenomenon has not been studied. Subjects were ascertained as a convenience sample through our clinic for persons with DS and medical or mental health concerns between 2004 and 2009. When mood symptoms were present an axis I diagnosis was made using DSM-IV-R criteria. Subjects without an axis I diagnosis served as controls. The Reiss scales for children's dual diagnosis and the aberrant behavior checklist (ABC) were completed by caretakers. Twenty-eight cases meeting criteria for major depressive episode (MDE) and nine controls without psychopathology were referred for overnight polysomnography (PSG). Functional decline was reported in 19 (68%) of cases with MDE, but none of the controls. Twenty-four (86%) cases had OSAS compared with only 4 (44%) of controls. Moderate–severe OSAS was present in 15 (54%) of cases compared to only 1 (11%) of controls. Intermittent sleep-associated hypoxia and REM sleep deficits were also more frequent in cases. Across all subjects, prior tonsillectomy was not related to the presence or absence of OSAS. Our findings suggest that OSAS may be a common co-morbidity in adolescents and younger adults with DS and depression. Recognition of this association maybe critical to understanding the pathogenesis and management of mood-related disorders, and functional decline in affected individuals. © 2013 Wiley Periodicals, Inc.