Pilocytic astrocytoma (PA) is the most common pediatric brain tumor. Most arise in the cerebellum, but they also can develop in the brainstem and optic nerve, where gross total resection (GTR) is not possible. In the absence of GTR, significant variability in both clinical behavior and histology exists. To identify potential markers associated with poor clinical outcome, we retrospectively assessed pathological features in 107 patients with PAs. We identified four pathological features (necrosis, oligodendroglioma-like features, vascular hyalinization, and calcification) that showed a significant correlation with decreased event-free survival (EFS). Similar to previous reports, we also found that PAs involving the optic pathway were associated with worse EFS compared with those arising in other locations. In contrast, mitotic index, p53 immunoreactivity and hyperactivation of several mitogenic signaling pathways (MAPK, CREB, mTOR) did not demonstrate a statistically significant relationship with EFS. Lastly, we did find a statistical trend between EFS and the number of CD68+ cells, suggesting that non-neoplastic elements of the tumor microenvironment may influence subsequent growth and clinical recurrence. Collectively, the identification of specific histopathologic features associated with clinical outcome may improve our ability to determine which PAs are more likely to exhibit clinical progression and require more vigilant observation.