ABSTRACT: The current study was performed to examine associations between childhood cancer therapies, chronic health conditions, and symptoms of emotional distress in adult survivors of childhood cancer.Participants included 5021 adult survivors of childhood cancer (mean age, 32.0 years [standard deviation, 7.6 years] with a time since diagnosis of 23.2 years [standard deviation, 4.5 years]) who completed measures assessing symptoms of anxiety, depression, and posttraumatic stress. Cardiac, pulmonary, and endocrine conditions were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.03; grades 1-4). Structural equation modeling was used to examine hypothesized pathways between cancer treatment exposures, chronic health conditions, and symptoms of emotional distress. Multivariable models were used to estimate relative risks (RRs) for associations between chronic health conditions and distress.Survivors with cardiovascular, endocrine, or pulmonary conditions were found to have a significantly higher prevalence of emotional distress symptoms. In path analyses and multivariable models, significant effects were observed between endocrine (??=?.12 [P?=?.002] and RR, 1.3 [95% confidence interval (95% CI), 1.1-1.6]) and pulmonary (??=?.13 [P<.001] and RR, 1.4 [95% CI, 1.1-1.7]) conditions and depression, and between cardiac (??=?.13 [P?=?.001] and RR, 1.5 [95% CI, 1.2-1.8]) and pulmonary (??=?.15 [P<.001] and RR, 1.6 [95% CI, 1.3-2.0]) conditions and anxiety. All treatment-related chronic health conditions were found to be associated with posttraumatic stress symptoms (cardiac: ??=?.09 [P?=?.004] and RR, 1.3 [95% CI, 1.2-1.5]; endocrine: ??=?.12 [P<.001] and RR, 1.3 [95% CI, 1.2-1.5]; and pulmonary: ??=?.13 [P<.001] and RR, 1.4 [95% CI, 1.2-1.6]).Chronic health conditions resulting from childhood cancer therapies contribute to emotional distress in adult survivors. Targeted mental health screening efforts in this at-risk population appear warranted. Therapeutic approaches should consider the complex interplay between chronic health conditions and symptoms of emotional distress. Cancer 2017;123:521-528. © 2016 American Cancer Society.