Background: Heat shock proteins (HSP) can be heat induced and when released into the extracellular environment, act as immunomodulatory molecules attracting antigen-presenting cells to the sites of immunogenetic peptides. Previous studies have isolated HSP from autologous melanoma tumors in vitro and then re-inoculated into patients as exogenous therapeutic vaccines. In this feasibility study, we attempt to create an endogenous HSP vaccine in patients with metastatic melanoma through the use of sublethal radiofrequency treatment (RFT, see below) and intra-lesional GM-CSF plus or minus subsequent ablation with radiofrequency ablation (RFA) or cryoablation. Methods: With IRB approval, consenting HLA-A2 positive patients with metastatic melanoma were placed into 1 of 3 cohorts. Cohort 1 received RFT (50°C for 30 minutes) to the target lesion followed by intra-lesional injection of 500 mcg of GM-CSF. Cohorts 2 and 3 received the same with the addition of tumor ablation (RFA in cohort 2 and cryoablation in cohort 3). Serum HSP70 was measured at baseline and every 3 hours for the first 24 hours. Melanoma specific tetramer analysis was performed on blood at baseline, 3 and 6 weeks postprocedure to evaluate for the primary endpoint of melanoma specific cytotoxic T lymphocyte (CTL) production. Positive tetramer results were identified by detection of a previously negative, or a doubling in value of a previously detected, melanoma specific CTL. Results: Nine patients (3 per cohort) completed the treatment. HSP70 levels doubled from baseline in 5 of 9 patients. Positive tetramer results were identified in 7 of 8 patients (1 patient in cohort 2 developed brain metastasis and had no tetramer testing). No patient received significant clinical benefit with median progression free survival and overall survival of 1.6 and 7.6 months respectively. No grade 3/4 adverse events attributable to the treatment were reported. Conclusions: Melanoma specific CTLs can be induced endogenously, but alone, this approach is not sufficient to affect clinical outcomes. However, this approach does appear effective in “priming” the immune system and may be complementary with other efforts aimed at non-specific activation of systemic T cells (e.g. ipilimumab).