The effectiveness of methotrexate eluted from polymethylmethacrylate on cell lines established from giant cell tumor of bone was investigated in vitro to determine the possible efficacy of this treatment. Elation of methotrexate from polymethylmethacrylate beads and boluses was shown in vitro to be dose dependent and limited by the size of the bolus. Cytocidal activity of methotrexate elated from polymethylmethacrylate beads prepared without monomer and of boluses of polymethylmethacrylate with the same dose of methotrexate prepared with monomer against 2 human giant cell tumor cell lines was statistically significant at 24 hours in culture. Statistical significance occurred at 24 hours in culture. Activity was maintained in vitro after 17 days. These experiments showed that eluted methotrexate remained effective against tumor cells after exposure to thermal changes during polymerization of polymethylmethacrylate. While extensive curettage of giant cell tumor of bone followed by filling in the defect with polymethylmethacrylate has become a common treatment, a local adjuvant is necessary to reduce further risk of local recurrence. A potential alternative to cryosurgery or instillation of phenol is the use of methotrexate impregnated polymethylmethacrylate to treat residual microscopic disease after curettage. This method may provide locally effective chemotherapy without the risks of systemic toxicities.