Regional infusion therapy with melphalan (LPAM) is an accepted treatment for advanced extremity melanoma. However, much room exists for improving the therapeutic index of this type of therapy.Isolated limb infusion (ILI) with temozolomide (TMZ), a novel methylating agent, was performed using a nude rat bearing human melanoma xenograft. Additional rats were treated systemically with TMZ, or regionally with LPAM or 10% dimethyl sulfoxide (DMSO; control) using ILI.Rats that received systemic TMZ showed a poor tumor response and no tumor regression. In contrast, intra-arterial TMZ demonstrated a prolongation of tumor growth delay in a dose-responsive manner. In comparison with LPAM of equitoxic dose, TMZ provided both longer tumor growth delay and a greater number of tumor regressions.These data suggest that ILI with TMZ is an effective treatment for advanced extremity melanoma and may be better than LPAM in this setting.