The retinoblastoma susceptibility gene (RB), the prototype of the class of tumor suppressor genes, is inactivated in a number of human malignancies. We investigated a possible role of RB in human brain tumors. Immunoprecipitation revealed frequent loss of RB protein expression in glioma cell lines (8/24), which was accompanied by lack of RB encoded transcripts. Among seventeen primary brain tumors studied by Western blotting, loss of Rb protein expression was observed in WHO grade 3 and 4 gliomas (3/10). However, none of the low grade gliomas and the other primary brain tumors investigated lacked RB protein expression. These data suggest a role for RB in glial malignancy, and loss of Rb expression appears to be associated with glial tumor progression.