Background: Fifteen to 20% of children with neurofibromatosis type 1 (NF1) develop low-grade astrocytomas. Although brain tumors are less common in teenagers and adults with NF1, recent studies have suggested that patients with NF1 are at a significantly increased risk of developing astrocytomas. Objectives: To investigate the genetic basis for astrocytoma development in patients with NF1 beyond the first decade of life. Methods: The authors performed molecular genetic analyses of 10 NF1-associated astrocytomas representing all World Health Organization (WHO) malignancy grades using fluorescence in situ hybridization, loss of heterozygosity, immunohistochemistry, and direct sequencing. Results: Later-onset NF1-associated astrocytomas, unlike histologically identical sporadic astrocytomas, exhibit NF1 inactivation, supporting a direct association with NF1 rather than a chance occurrence. Furthermore, some of these astrocytomas have homozygous NF1 deletion. In addition, genetic changes observed in high-grade sporadic astrocytomas, including TP53 mutation and CDKN2A/p16 deletion, are also seen in NF1-associated high-grade astrocytomas. Conclusions: Neurofibromatosis type 1-associated astrocytomas occurring in patients older than 10 years exhibit genetic changes observed in sporadic high-grade astrocytomas. Patients with neurofibromatosis type 1 and germline NF1 deletions may be at risk for developing late-onset astrocytomas.