We present two phenotypically similar females with Xp duplication who have autism and epilepsy. Case 1 is a 14-year-old Honduran female with autism and medically refractory complex partial, secondarily generalized epilepsy. Case 2 is a 3-year-old Austrian female with autism and medically refractory complex partial epilepsy. Both patients also share features of severe intellectual disability (case 1 has a developmental quotient of 23, case 2 has a developmental quotient of 42) and dysmorphic facial features. Autism was confirmed by thorough clinical evaluations and testing. Case 1 has a karyotype of 46,X,dup(X)(p11.2-p22.33) and a highly skewed X-inactivation pattern (94:6). Brain magnetic resonance imaging (MRI) and electroencephalogram (EEG) were abnormal. Case 2 has a 5-megabase duplication of Xp11.22-p11.23 on chromosome microarray analysis. The patient has a random X-inactivation pattern (77:23). Brain MRI was normal, but EEG was abnormal. Both patients have duplications involving the Xp11.22-p11.23 region, indicating that this is an area of interest for future translational autism research.