To our knowledge this is the first reported case of postural orthostatic tachycardia syndrome (POTS) in a patient with Klinefelter syndrome. We describe a classic clinical presentation of POTS in an adolescent male with Klinefelter syndrome. Although the etiology of POTS appears to be multifactorial, there is a strong female predominance that suggests a genetic basis. Our patient with Klinefelter syndrome may further support a link with POTS to the X chromosome.