BACKGROUND. Klinefelter syndrome is the most frequent chromosomal aneuploidy with a prevalence of 1 in 700. Klinefelter syndrome has been widely associated with cognitive impairment and language problems. No previous studies have systematically investigated the association of Klinefelter syndrome with psychiatric disorders in children and adolescents. To our knowledge, the only data available are from psychiatric inventories of adults with Klinefelter syndrome. OBJECTIVE. To explore the extent of psychiatric morbidity in children with Klinefelter syndrome. METHOD. Fifty-one subjects with Klinefelter syndrome aged 6 to 19 years were included through the Dutch Klinefelter association and 2 university medical centers. The sample was screened by using structured and standardized assessment procedures covering the full range of psychiatric problems and disorders. In addition, all boys were formally evaluated for the presence of a language disorder. RESULTS. A wide range of classifications could be applied, with language disorder (65% [33 of 51]) as the most prevalent disorder, followed by attention-deficit disorders (63% [32 of 51]) and autism spectrum disorder (27% [14 of 51]). Behavioral impairment was most evident among cases classified as autism spectrum disorder and psychotic disorder (12% [6 of 51]). CONCLUSIONS. Children with Klinefelter syndrome seem to be at risk for problems in social and language development, as well as for problems in regulation of emotion and behavior. This is reflected in the broad spectrum of psychiatric classifications applicable in the present selected sample. Health care professionals should be aware of an increased a priori possibility of psychiatric problems when confronted with a child with Klinefelter syndrome.