OBJECTIVE: To distinguish the clinical manifestations and natural history of optic pathway tumors (OPT) associated with neurofibromatosis type 1 (NF-1 OPT) from that of OPT not associated with NF-1 (non-NF-1 OPT). METHODS: Two groups of children with OPT were compared: (1) 17 children with NF-1 OPT who were followed prospectively, and (2) 19 children with non-NF-1 OPT who were identified retrospectively by a review of medical records. RESULTS: Precocious puberty was a common initial sign in the children with NF-1 OPT (5/17), and was not found in any patients without NF-1. In contrast, children with non-NF-1 OPT had symptoms attributable to increased intracranial pressure (12/19 and nystagmus (5/19); these symptoms were not found in any patient with NF-1. Decreased visual acuity at the time of diagnosis was common in both groups. There was no significant difference between the children with NF-1 OPT and those with non-NF-1 OPT as to age at diagnosis or sex distribution. Optic nerve involvement was more common in NF-1 (p < 0.001). Both isolated and bilateral optic nerve tumors were found exclusively in children with NF-1, whereas chiasmal (p = 0.016) and optic tract involvement (p = 0.001) were more common in those with non-NF-1 OPT. Radiographic evidence of hydrocephalus was found in none of the children with NF-1 OPT compared with 79% of the non-NF-1 OPT group. Progressive disease was seen in 12% of patients with NF-1 OPT compared with 63% of those with non-NF-1 OPT. CONCLUSIONS: Differences exist between NF-1 OPT and non-NF-1 OPT both at the time of diagnosis and during follow-up. Optic pathway tumors caused by NF-1 and non-NF-1 OPT have different biologic properties that distinguish both their initial clinical manifestations and their natural history.