PURPOSE: Childhood acute lymphoblastic leukemia (ALL) is treated with potentially neurotoxic drugs and neurologic complications in long-term survivors are inadequately studied. This study investigated neurologic morbidity and its effect on quality of life in long-term survivors of childhood ALL. METHODS: Prospective, single institution, cross-sectional, institutional review board-approved study of long-term ALL survivors. Participants were recruited from institutional clinics. Participants answered an investigator-administered questionnaire followed by evaluation by a neurologist. Quality of life (QOL) was also assessed. RESULTS: Of the 162 participants recruited over a 3-year period, 83.3% reported at least one neurologic symptom of interest, 16.7% had single symptom, 11.1% had two symptoms, and 55.6% had three or more symptoms. Symptoms were mild and disability was low in the majority of participants with neurologic symptoms. Median age at ALL diagnosis was 3.9 years (0.4-18.6), median age at study enrollment was 15.7 years (6.9-28.9), and median time from completion of ALL therapy was 7.4 years (1.9-20.3). On multivariable analyses, female sex correlated with presence of dizziness, urinary incontinence, constipation, and neuropathy; use of ≥10 doses of triple intrathecal chemotherapy correlated with urinary incontinence, back pain, and neuropathy; cranial radiation with ataxia; history of ALL relapse with fatigue; and CNS leukemia at diagnosis with seizures. Decline in mental QOL was associated with migraine and tension type headaches, while physical QOL was impaired by presence of dizziness and falls. Overall, good QOL and physical function was maintained by a majority of participants. CONCLUSIONS: Neurologic symptoms were present in 83% long-term ALL survivors. Symptoms related morbidity and QOL impairment is low in majority of survivors. Female sex, ≥10 doses of intrathecal chemotherapy, and history of ALL relapse predispose to impaired QOL. IMPLICATIONS FOR CANCER SURVIVORS: This study will educate survivors and their care providers regarding cancer or treatment-related neurologic symptoms and morbidity. This study will help them understand factors contributing to impaired QOL when present.