The presence of gemistocytes in low-grade astrocytomas is regarded as a sign of poor prognosis because the majority of gemistocytic astrocytomas rapidly progress to anaplastic astrocytoma or glioblastoma. To elucidate the role of gemistocytes in astrocytoma progression, we assessed the fraction of neoplastic gemistocytes, bcl-2 expression, p53 mutations, p53 immunoreactivity (PAb 1801), and proliferative activity (MIB-1) in 40 low-grade astrocytomas (World Health Organization (WHO) Grade II) with histologically proven progression to anaplastic astrocytoma (WHC Grade III) or glioblastoma (WHO Grade IV). Astrocytoma progression took significantly less time in patients with a low-grade astrocytoma containing more than 5% gemistocytes (35 months) than in those with lesions containing less than 5% gemistocytes (64 months; p = 0.038). All 11 astrocytomas with more than 5% gemistocytes contained a p53 mutation, whereas the incidence of p53 mutations in astrocytomas with less than 5% gemistocytes was 61% (p = 0.017). In low-grade astrocytomas the p53 labeling index (LI) of gemistocytes (7.4%) was significantly higher than in all tumor cells (3.2%, p = 0.0014). Gemistocytes showed a significantly higher bcl-2 expression than all tumor cells, with a mean bcl-2 1 of 15.6% versus 2.7% in low-grade astrocytomas (p = 0.0004), 20.9% versus 3.0% in anaplastic astrocytoma (p = 0.002), and 30.2% versus 5.2% in glioblastomas (p = 0.0002). In contrast, gemistocytes showed a significantly lower proliferating activity than the mean of all tumor cells, with a mean MIB-1 LI of 0.5% versus 2.6% in low-grade astrocytomas, 1.5% versus 11.6% in anaplastic astrocytoma, and 1.7% versus 16.6% in glioblastomas (p < 0.0001). These data show that low-grade astrocytomas with a significant fraction of gemistocytes progress more rapidly and typically carry a p53 mutation. The vast majority of gemistocytes are, however, in a nonproliferative state (G0 phase of the cell cycle), which suggests terminal differentiation. Their accumulation within astrocytomas may be due to bcl-2-mediated escape from apoptosis.