Melanoma is the fastest rising cancer in the United States. Bacillus Calmette-Guerin (BCG) has been genetically engineered to actively express and secrete the cytokine interleukin-2 (IL-2). Both BCG and IL-2 have known potent antitumor and immunomodulatory properties.This recombinant BCG (rBCG 3A) has been tested as an intratumoral injection and a vaccine therapy in conjunction with irradiated tumor cells against melanoma in the murine B16 melanoma model.The transfection process did not adversely alter the function of the wild-type (WT) BCG. rBCG 3A and WT BCG are equally effective intratumoral and vaccine therapies against melanoma when compared with normal saline control groups. Tumor burdens were significantly smaller (p < or = 0.01 and 0.05) for the treatment groups for both intratumoral and vaccine administration of therapy. Immunization with rBCG 3A and WT BCG 14 days before a B16 challenge resulted in an approximately 45% smaller tumor burden when compared with controls.Novel therapies based on the immunogenic properties of melanoma combined with molecular technologies may offer promise for an effective and safe treatment of melanoma.