Abstract Various published data show that in patients with metastatic melanoma, high-dose interleukin-2 (IL2) is associated with 5-year survival rates of 15% from treatment initiation. We previously reported a median survival of 15.6 months, and a 20% 5-year survival rate for 150 patients who were treated with inpatient IL2 (Cancer Biother Radiopharm 2012;27:337). In the current study, we sought to determine whether treatment with active specific immunotherapy (ASI) with patient-specific tumor stem cell vaccines derived from autologous tumor cell (TC) lines contributed to the survival result. Existing databases revealed that 32/149 IL2-treated patients also received ASI, while 117 did not. ASI was given within 12 months of IL2 therapy in 19/32 patients. Patients who received IL2 plus ASI had better overall survival (p<0.001) with longer median survival (39.5 vs. 12.0 months) and a higher 5-year survival rate (39% vs. 13%). Survival was better even after exclusion of 55 IL2-alone patients who died before 12 months of follow-up (p=0.12). In subset analyses, survival was longer for 25 patients who received ASI after IL2 than for 7 who received ASI before IL2 (5-year survival 46% vs. 14%, p<0.001) and for 16 patients who received a dendritic cell/TC-based ASI compared with 16 injected with irradiated TC (p=0.17). This retrospective study suggests that receipt of IL2 followed by a patient-specific melanoma stem cell vaccine is associated with better survival than IL2 alone.