We present the first case-control study addressing both fracture occurrence and fracture mechanisms in Rett syndrome (RTT). Two previous studies have shown increased fracture risk in RTT. This was also our hypothesis regarding the Danish RTT population. Therefore, we investigated risk factors associated with low-energy trauma and the association to methyl-CpG-binding protein 2 (MECP2) mutations. A total of 61 female patients with RTT and 122 healthy controls matched according to age and pubertal/menopause status were examined by questionnaires, bone biochemical markers in blood, and clinical and x-ray evaluations. National register search on fracture diagnoses was done to obtain complete fracture histories. Our results showed that patients with RTT sustained significantly more low-energy fractures from early age compared with controls, even though overall fracture occurrence apparently was not increased. Low-energy fractures were significantly associated with less mobility and lack of ambulation. Associations with MECP2 mutations or epilepsy were not demonstrated, contrary to previous findings. Blood biochemistry indicated a possible need for D vitamin supplementation in RTT. Our study casts light on fracture occurrence in RTT and points to a need for future research in bone development and fracture risk to establish directions for improved prevention and treatment of low-energy fractures in RTT.