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Adult survivors of childhood cancer are at risk for long-term morbidities, which may be managed pharmacologically. Psychoactive medication treatment has been associated with adverse effects on specific neurocognitive processes in non-cancer populations, yet these associations have not been examined in adult survivors of childhood cancer.Outcomes were evaluated in 7,080 adult survivors from the Childhood Cancer Survivor Study (CCSS) using a validated self-report Neurocognitive Questionnaire. Multivariable logistic regression models were used to calculate odds ratios (OR) and 95% confidence intervals (CI) for neurocognitive impairment using demographic and treatment factors and survivors' report of prescription medication use.Controlling for cranial radiation, pain, psychological distress, and stroke/seizure, use of antidepressant medications was associated with impaired task efficiency (OR = 1.80, 95% CI = 1.47–2.21), organization (OR = 1.83, 95% CI = 1.48–2.25), memory (OR = 1.53, 95% CI = 1.27–1.84), and emotional regulation (OR = 2.06, 95% CI = 1.70–2.51). Neuroleptics and stimulants were associated with impaired task efficiency (OR = 2.46, 95% CI = 1.29–4.69; OR = 2.82, 95% CI = 1.61–4.93, respectively) and memory (OR = 2.08, 95% CI = 1.13–3.82; OR = 2.69, 95% CI = 1.59–4.54, respectively). Anticonvulsants were associated with impaired task efficiency, memory, and emotional regulation, although survivors who use these medications may be at risk for neurocognitive impairment on the basis of seizure disorder and/or underlying tumor location (CNS).These findings suggest that specific psychoactive medications and/or mental health conditions may be associated with neurocognitive function in adult survivors of childhood cancer. The extent to which these associations are causal or indicative of underlying neurological impairment for which the medications are prescribed remains to be ascertained. Pediatr Blood Cancer 2013; 60: 486–493. © 2012 Wiley Periodicals, Inc.