Inclusion Criteria: 1. Men, 18 - 85 years of age 2. Castrate testosterone level < 50 ng/dl. Currently using a GnRH agonist or antagonist unless surgically castrated 3. Metastatic prostate cancer with progressive disease post surgical castration, or during androgen suppression therapy (or complete androgen blockade therapy and withdrawal) - Radiological progression consistent with prostate cancer. - PSA progression defined as 2 separate increasing values one week apart and > 2.0 ng/dl 4. PSA doubling time of >1 month within 6 months of the anticipated first dose 5. Chemotherapy naïve 6. Vaccinia-experienced (previous smallpox vaccination) 7. ECOG Performance Score of 0 or 1 8. Life expectancy ≥ 1 year 9. Adequate bone marrow, hepatic and renal function Exclusion Criteria: 1. Cancer-related pain requiring scheduled opioid narcotics for control 2. Metastasis to sites other than lymph nodes and/or bone 3. LDH or alkaline phosphatase ≥ 2 times ULN 4. Concurrent or prior Provenge (sipuleucel-T) immunotherapy 5. Receipt of an investigational agent within 30 days (60 days for an antibody-based therapy) of the first planned dose of study vaccine 6. Prior malignancies other than prostate cancer within the past 3 years 7. CHF (NYHA Class II, III, or IV), unstable angina, ventricular or hemodynamically significant atrial arrhythmia, or CVD such as stroke or MI 8. Confirmed positive for HIV, hepatitis B, and /or hepatitis C 9. Immunodeficiency or splenectomy 10. Concurrent immunosuppressive therapy 11. History of or active autoimmune disease 12. Known allergy to eggs, egg products, aminoglycoside antibiotics, or GM-CSF. 13. History of atopic dermatitis or active skin condition that disrupts the epidermis 14. Previous adverse reactions to smallpox vaccination 15. Unable to avoid close contact with the high-risk individuals for three weeks after the Day 1 vaccination: (a) children ≤ 3 year of age, (b) pregnant or nursing women, (c) individuals with prior or concurrent extensive eczema or other eczematous skin disorders, or (d) immunocompromised individuals (HIV). 16. Inflammatory eye disease requiring steroid treatment 17. Estimate PSA doubling time of <1 month as established within 6 mos of the anticipated first dose of vaccine or placebo. 18. Study personnel