BACKGROUND:With increased cure, childhood cancer survivors are reaching adulthood and seeking employment. Host, disease and treatment risk factors may contribute to inability to attain or maintain employment. PROCEDURE:The prevalence and risk factors for unemployment were evaluated using self-reported employment history in 10,399 childhood cancer survivors and 3,083 siblings >/= age 18 in the Childhood Cancer Survivor Study (CCSS). RESULTS:Among survivors, 5.6% reported unemployment, compared with 1.2% of siblings (odds ratio [OR] 3.7; 95% confidence interval [CI] 2.6, 5.1). Increased risks were observed within all cancer diagnoses. In multivariate analysis, diagnosis of central nervous system (CNS) tumor (OR 1.5; 95% CI 1.1, 2.1), bone cancer (OR 1.5; 95% CI 1.0, 2.1), treatment with >/=30 Gy cranial radiotherapy (OR 4.0; 95% CI 2.9, 5.5), female gender (OR 1.4; 95% CI 1.2, 1.7) and age < 4 years at diagnosis (OR 1.4; 95% CI 1.1, 1.8) increased risk. Diagnosis of CNS or bone tumor or cranial radiotherapy >/=30 Gy remained significant after adjusting for treatment, medical late effects, age and gender. Risk of unemployment decreased with attained age (OR((year)) 0.89; 95% CI 0.87, 0.91). CONCLUSIONS:Compared to siblings, adult childhood cancer survivors are at increased risk for unemployment with highest risk defined by diagnosis, treatment and demographic factors.