Purpose: The efficacy of immunotherapy against advanced cancer may be improved by combination strategies. Photodynamic therapy (PDT) is a local tumor ablation method based on localized activation of a photosensitizer, leading to oxygen radical-induced tumor cell death. PDT can enhance antitumor immune responses by release of antigen and danger signals, supporting combination protocols of PDT with immunotherapy. Experimental Design: We investigated the local and systemic immune effects of PDT after treatment of established tumors. In two independent aggressivemouse tumor models, TC-1 andRMA, we combined PDT with therapeutic vaccination using synthetic long peptides (SLP) containing epitopes from tumor antigens. Results: PDT of established tumors using the photosensitizer Bremachlorin resulted in significant delay of tumor outgrowth. Combination treatment of PDT with therapeutic SLP vaccination cured one third of mice. Importantly, all cured mice were fully protected against subsequent tumor rechallenge, and combination treatment of primary tumors led to eradication of distant secondary tumors, indicating the induction of a systemic antitumor immune response. Indeed, PDT by itself induced a significant CD8+ T-cell response against the tumor, which was increased when combined with SLP vaccination and essential for the therapeutic effect of combination therapy. Conclusions: We show that immunotherapy can be efficiently combined with PDT to eradicate established tumors, based on strong local tumor ablation and the induction of a robust systemic immune response. These results suggest combination of active immunotherapy with tumor ablation by PDT as a feasible novel treatment strategy for advanced cancer. Clin Cancer Res; 22(6); 1459-68.