BACKGROUND: Angelman syndrome (AS) is a developmental disorder caused by one of four molecular etiologies. Affected individuals have intellectual disability (ID), limited speech, seizures, and sleep problems. Parents of individuals with AS exhibit elevated stress compared to parents of individuals with other IDs. We examined parental stress and family quality of life (FQOL) over time in families of individuals living with AS. METHODS: Data were collected in a natural history study of AS. The Parenting Stress Index, Third Edition (PSI) and the Beach Center FQOL scale assessed parent stress and FQOL. Stress and FQOL were examined across AS molecular subtypes, and predictors were analyzed using a generalised linear model. Relationships between parental stress and FQOL were examined using Pearson correlations and a stepwise mixed-linear model approach. RESULTS: Our sample consisted of 231 families of individuals living with AS. Parental stress was clinically elevated and was highest in families of individuals with CONCLUSIONS: Stress is elevated in parents of individuals with AS across subtypes and has a small negative impact on family quality of life. Interventions to reduce stress have potential to improve individual and family well-being.