Inclusion Criteria:
* Histologically-confirmed, advanced/metastatic colorectal carcinoma
* Failed both oxaliplatin and irinotecan based regimens for advanced/metastatic disease (if tumor advanced either immediately or within 3 months of the end of treatment)
* Resistance to Erbitux: patients with Ras mutations, or for whom Erbitux has failed (if tumor advanced either immediately or within 3 months of the end of treatment, or there is no response to Erbitux therapy due to a lack of expression of EGFR (epidermal growth factor))
* Karnofsky Performance Score (KPS) ≥ 70
* Age ≥18 years
* Laboratory Safety: WBC ≥ 3,500 cells/mm3 and ≤ 50,000 cells/mm3, ANC ≥ 1,500 cells/mm3, Hemoglobin ≥ 10 g/dL (transfusion allowed), Platelet count ≥ 100,000 plts/mm3,Total bilirubin ≤ 1.5 X ULN, INR ≤ 1.5, AST, ALT ≤ 2.5x ULN (in case of liver metastasis: AST,ALT ≤5.0 x ULN)
* Serum chemistries within normal limits (WNL) or Grade 1 (excluding alkaline phosphatase) - If patients are diabetic, a fasting glucose must be done and patients must be \> 160 mg/dL.
* Patients who, if they are sexually active, are willing and able to refrain from sexual activity for 3 weeks following JX-594 administration. Patients who are willing and able to use a permitted contraceptive for 3 months after the final administration of JX-594.
Exclusion Criteria:
* Significant immunodeficiency due to underlying illness (e.g. HIV/AIDS) and/or medication (e.g. systemic corticosteroids)
* Known myeloproliferative disorders requiring systemic therapy
* History of exfoliative skin condition (e.g. eczema or ectopic dermatitis) requiring systemic therapy
* History of acquiring opportunistic infections.
* Tumor(s) invading a major vascular structure (e.g. carotid artery)
* Tumor(s) in location that would potentially result in significant clinical adverse effects if post-treatment tumor swelling were to occur
* Clinically uncontrolled and/or rapidly accumulating ascites, pericardial and/or pleural effusions
* History of severe or unstable cardiac disease
* Current, known CNS malignancy (history of completely resected or irradiated brain metastases by WBRT or stereotactic radiosurgery allowed)
* Administered anti-cancer therapy within 4 weeks prior to first treatment (6 weeks in case of mitomycin C or nitrosoureas)
* Use of anti-viral, anti-platelet, or anti-coagulation medication \[Patients who discontinue such medications within 7 days prior to first treatment may be eligible for this study.\] Low dose aspirin (approximately 81 mg) allowed.
* Pulse oximetry O2 saturation \<90% Pulse oximetry O2 saturation \<90% at rest
* Experienced a severe systemic reaction or side-effect as a result of a previous smallpox vaccination
* Pregnant or nursing
* Household contact exclusions:
* Women who are pregnant or nursing an infant
* Children \< 5 years old
* People with skin disease (e.g. eczema, atopic dermatitis, and related diseases
* Immunocompromised hosts (severe deficiencies in cell-mediated immunity, including AIDS, organ transplant recipients, hematologic malignancies)
