Background: Congenital central hypoventilation syndrome (CCHS) is a rare genetic disease due to PHOX2B mutations. CCHS patients suffer from many autonomic disorders, dominated clinically by defective ventilatory automatisms. From birth, the life of CCHS patients depends on ventilatory support during sleep, involving a high burden of care. Whether or not this impairs the quality of life of these patients during adulthood remains unknown. Methods: We applied the medical outcome study short form-36 (SF-36) to 12 CCHS patients aged 15–33 (9 women) at the time of their passage from pediatric to adult care. Scores for the SF-36 dimensions were compared to the age-and gender-matched French reference population after transformation into standardized Z-scores. The SF-36 physical component summary score (PCS) and mental component summary score (MCS) were compared to American reference values. Results: Median Z-scores were significantly different from zero for PF (physical functioning, p = 0.020) and GH (general health perception, p = 0.0342) and for PCS (p = 0.020). The other physical dimensions (RP, role limitation due to physical function; BP, bodily pain) and the mental dimensions (VT, vitality; SF, social functioning; RE, role limitation due to emotional function; MH, mental health) and MCS were not altered. Conclusions: We conclude that, despite the physical constraints imposed by CCHS and its anxiogenic nature, this disease is associated with an impairment of health-related quality of life in young adults that remains moderate. Whatever the underlying explanations, these results convey hope to parents with a child diagnosed with CCHS and for patients themselves.