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Gestational exposure to famine has been associated with several chronic diseases in adulthood, but few studies in humans have related prenatal famine exposure to health-related quality of life. We used the circumstances of the Dutch Famine of 1944–1945 (during which official rations were <900 kcal/day for 24 weeks) to assess whether exposure to famine prior to conception or at specified stages of pregnancy was related to self-reported health-related quality of life and depressive symptoms in adulthood.We studied 923 individuals, including persons born in western Holland between January 1945 and March 1946, persons born in the same 3 institutions in 1943 and 1947 and same-sex siblings of persons in series 1 or 2. Between 2003 and 2005 (mean age: 59 years), we assessed self-reported quality of life with the Short Form 36 questionnaire and derived mental and physical component scores. Depressive symptoms were assessed with the Center for Epidemiologic Studies Depression scale.Mean mental and physical component scores were 52.4 (SD = 9.4) and 48.9 (9.0), respectively. The mean depression score was 11.6 (7.4). Age-, sex-, and schooling-adjusted estimates for mutually adjusted exposures were −2.48 for the mental component score with exposure before conception (95% confidence interval = −4.46 to −0.50) and 0.07 with exposure during pregnancy (−1.15 to 1.29). Adjusted estimates for the physical component score were 1.26 with exposure before conception (−0.67 to 3.19) and −0.73 with exposure during pregnancy (−1.94 to 0.48). Adjusted estimates for the depression score were 2.07 with exposure before conception (0.60 to 3.54) and 0.96 with exposure during pregnancy (0.09 to 1.88). There was no evidence of heterogeneity of effects by specific periods of pregnancy exposed to famine.A mother's exposure to famine prior to conception of her offspring was associated with lower self-reported measures of mental health and quality of life in her adult offspring.