Information received from the review of scientific literature on 12APR2019. This article presents a case of Acute Myeloid Leukemia in a male who reported receiving smallpox vaccination as a part of smallpox vaccination policy in preparation for an overseas assignment. This literature case involves a 19 years old male who received smallpox vaccination on an unknown date in January 2016 as a part of smallpox vaccination policy for overseas assignment preparation. On day 1, post vaccination, patient experienced activity-limiting malaise, odynophagia, and retrosternal chest pain which was treated with Ranitidine. He also developed fevers, cough and rhinorrhea which was attributed to upper respiratory infection on day 5 post vaccination. Initial examination of the vaccination side on day 8, post vaccination, showed an expected major reaction. On post vaccination day (PVD) 11, patient had developed a central scotoma without conjunctival injection or lesion, erythema worsening around the site of smallpox vaccination and a new scalp lesion. PVD 12, revealed pancytopenia with peripheral blood smear demonstrating 35-40% circulating blasts. The male patient was sent to a Medical Center for further investigation of Acute leukemia and initial concern for disseminated vaccinia virus infection. On PVD 13, the patient had fatigue, pancytopenia, right scalp papule, a new flank papule and a normal vaccination site lesion at his left deltoid surrounded by petechiae which were in a bandage shaped distribution. Polymerase chain reaction (PCR) tests were done with the swabs of flank and scalp lesions and were sent to the CDC and it revealed Orthopox virus DNA at both the sites. No orthopoxvirus DNA was detected by PCR in either bone marrow aspirate or blood samples, thus it lowered the suspicion for disseminated vaccinia. Patient developed central scotoma attributed to thrombocytopenic retinopathy without any evidence of ocular vaccinia virus infection. The diagnosis of Amyloid Leukemia (AML) was confirmed by peripheral blood cytometry and bone marrow biopsy. On PVD 15, patient was administered Vaccinia immune globulin intravenous (VIGIV) at a dose of 6000 units/Kg due to the risk of Progressive Vaccinia (PV) with induction chemotherapy. On the next day, the patient was started on a treatment simultaneously with oral Tecovirimat (ST-246), an anti-orthopoxvirus drug administered under an expanded access investigational new drug (IND) as well as a 7+3 regimen of Daunorubicin and Cytarabine. The CDC's IND protocol was amended and approved by the institutional review board for oral Tecovirimat to reflect the recommended dose of 600 mg orally twice daily and the patient was provided informed consent. Along with the clinical evaluation, patient was regularly monitored for the orthopoxvirus specific IgG and IgM antibody titers and orthopoxvirus DNA through venipuncture and swabs tests. On PVD 32 and 56 additional doses of VIGIV were administered due to his immunosuppression and decrease in the orthopoxvirus specific antibody titers. The clinical resolution of the inoculation site lead to the discontinuation of the oral Tecovirimat on PVD 77 (after 62 days and 123 doses). Pharmacokinetic monitoring revealed that patient had achieved adequate Tecovirimat exposure. Patient's hospitalization was complicated due to the intermittent episode of neutropenic fever, treated with several courses of broad-spectrum antibiotics without the determination of a clear source of infection. A negative blood orthopoxvirus PCR ruled out the viremic dissemination of vaccinia. Patient also developed non-oliguric kidney injury which was resolved with intravenous fluids and a morbilliform rash which resolved without any intervention. The hospital course was also marked by prolonged cytopenia. Post vaccination day 47, the patient was transferred to another hospital where he began with the consolidation chemotherapy with Idarubicin and Cytarabine 3 months after the vaccination. Patient finally underwent an allogenic stem cell transplant 5 months after the presentation. There was no evidence of recurrence of vaccinia virus infection through his last follow up, 20 months after the vaccination. Treatments included: Ranitidine; VIGIV 6000 units/kg due to risk of PV, 7+3 regimen of Daunorubicin and Cytarabine, Oral and topical Tecovirimat (ST-246), Broad spectrum antibiotics, Intravenous Fluids, oral CMX001 (Brincidofovir). Medical History and Drug Allergies: There was no known drug allergy and medical history for the patient. Relevant Laboratory/Diagnostics: Peripheral Blood smear demonstrated 30-40% circulating blasts, Polymerase chain reaction for orthopoxvirus DNA, Peripheral blood cytometry, Bone marrow biopsy, Venipuncture and swab tests for the IgG and IgM antibody titers.