Objectives To investigate risk factors for seizure onset in Rett syndrome.Study design Information on presence and age at onset of seizures, perinatal and developmental history, and genetic status was abstracted on 275 cases in the Australian Rett Syndrome Database. Cox and Weibull regression were used to investigate and provide a model for predicting the effects of genetic and developmental factors on age at seizure onset.Results Seizures were reported in 81% of 275 cases; the median age of onset was 48 months. Not having gained the ability to walk (P = .003) and developmental problems in the first 10 months of age (P = .04) were associated with an almost 2-fold increased risk of seizures. Cases without a detectable MECP2 mutation had a higher risk of seizure onset up to 4 years of age (P < .001) but a lower risk after 4 years (P =.08).Conclusions Seizure onset in Rett syndrome is associated with early developmental factors and with genotype. Information on these factors can be used to predict age at seizure onset after diagnosis.