BACKGROUND: Adult survivors of childhood cancer and their siblings are compared on one of the most salient developmental milestones of adulthood, the ability to live independently. PROCEDURE: Adult survivors of childhood cancers (n = 6,047) and siblings (n = 2,326), all 25 years of age and older, completed a long-term follow-up questionnaire that assessed adaptive, neurocognitive, and psychological functioning, as well as demographic and health status. Multivariable logistic regression analyses and structural equation modeling (SEM) were used to identify predictors of independent living. RESULTS: Compared to siblings (n = 206, 8.7%), survivors (n = 1063; 17.7%) were more than twice as likely to live dependently (OR 2.07; 95% confidence interval [CI] 1.77-2.42). Survivors diagnosed with CNS tumors (OR 0.13, 95% CI 0.10-0.18) or leukemia (OR 0.29, 95% CI 0.23-0.27) were significantly less likely to live independently compared to those diagnosed with Hodgkin lymphoma. Other risk factors for reduced independent living included cranial radiation (= 24 Gy OR 0.76, 95% CI 0.62-0.93; >24 Gy OR 0.31, 95% CI 0.24-0.41), use of neuroleptic, anticonvulsant, or psychostimulant medication (OR 0.32, 95% CI 0.24-0.43), attention and processing speed problems (OR 0.58, 95% CI 0.47-0.71), poor physical functioning (OR 0.49, 95% CI 0.38-0.63), depression (OR 0.68, 95% CI 0.53-0.88), and racial/ethnic minority status (OR 0.39, 95% CI 0.30-0.51). SEM demonstrated that neurocognitive functioning had both direct effects on independent living status, and indirect effects through use of neurologically directed medication, depression, and poor mental health. CONCLUSION: Adult survivors of childhood cancer who experience neurocognitive, psychological, or physical late effects are less likely to live independently as adults.