BACKGROUND Few studies have assessed quality of life (QOL) for children born with major structural congenital anomalies. We aimed to review studies reporting QOL in children and adults born with selected congenital anomalies involving the digestive system. METHODS Systematic review methods were applied to literature searches, development of the data extraction protocol, and the review process. We included studies published in English (1990–2010), which used validated instruments to assess QOL in individuals born with congenital diaphragmatic hernia, esophageal atresia, duodenal atresia or abdominal wall defects. RESULTS Of 200 papers identified through literature searches, 111 were excluded after applying restrictions and removing duplicates. After scanning 89 abstracts, 32 full-text papers were reviewed (none on duodenal atresia), of which 18 (nine in children or adolescents and nine in adults) were included. Studies measured health-related QOL, but did not assess subjective wellbeing. Instruments used to assess health-related QOL in children varied considerably. In adults most studies used the Short Form 36. Many studies had methodological limitations, such as being from a single institution, retrospective cohorts, and low sample size. The summarized evidence suggests that health-related QOL of these children is affected by associated anomalies and ongoing morbidity resulting in lower physical functioning and general health perception. In adults, health-related QOL is comparable with the general population. CONCLUSIONS The reviewed studies considered health status and functioning as a major determinant of QOL. More studies assessing QOL in patients with major congenital anomalies are needed, and those involving children should use age-adjusted, validated instruments to measure both health-related QOL and self-reported subjective wellbeing. Birth Defects Research (Part A) 2012. © 2012 Wiley Periodicals, Inc.