Introduction: Acute panmyelosis with myelofibrosis (APMF) is rare yet a fatal hematological malignancy. It had been classified as a subtype of acute myeloid leukemia (AML) under the category "AML, not otherwise specified" in the WHO classification of hematological tumors. APMF usually presents with cytopenia without any marked splenomegaly. We report a case of an 80-year-old female who presented with generalized weakness. An extensive workup unmasked the presence of acute panmyelosis with myelofibrosis. Case Report: An 80-year-old female patient with history of epilepsy, essential hypertension, and hyperlipidemia presented to the clinic for generalized weakness and confusion for two weeks. She was also having dyspnea, initially on exertion, which progressed to even at rest for the last one week and was unable to ambulate without assistance. The patient also reported easy bruising with minor trauma and bruises on the upper extremity. The patient denied having any fever, chills, chest pain, orthopnea, dizziness, loss of consciousness, history of bleeding, or weight loss. On physical examination, the patient did not have enlarged lymph nodes or hepatosplenomegaly. Initial labs showed hemoglobin of 4.8 g/dL, platelets 5K/uL, a white blood count of 1.8 K/uL with differentials of 49% segmented neutrophils, 0.85 K/uL absolute neutrophils, 4% band cells, 44% lymphocytes, 1% myelocytes, 1% nucleated RBC's, 0.09 K/uL absolute monocytes, and 3% monocytes. Her absolute reticulocyte count was 0. Red blood cells were hypochromic with anisopoikilocytosis. The coagulation profile showed PT 16.5 seconds, INR 1.4, and aPTT 37 seconds. She also underwent a CT head for the confusion which was unremarkable. Chest x-ray revealed left mid & lower zone infiltrates consistent with pneumonia and the patient was given ceftriaxone. The patient was transfused irradiated packed red blood cells. There was a concern for bone marrow disorders such as myelodysplastic syndrome and leukemia, so the patient underwent a bone marrow biopsy. Flow cytometry of bone marrow aspirate revealed no significant blast cells; however, it showed myeloid neoplasm with myelofibrosis and proliferation of the atypical megakaryocytes with variable hypercellularity and diffusely marked reticulin fibrosis. Immunohistochemistry was positive for E-cadherin on megaloblastic erythroid, myeloperoxidase (highlighted patchy foci of maturing myeloid cells), CD34 (widespread positive in the atypical megakaryocyte, but not blast cells), and CD61 (GPIIIA). These findings along with the absence of splenomegaly were consistent with Panmyelosis with myelofibrosis. After the family discussion about chemotherapy and bone marrow transplant, a combined decision was made for hospice with comfort measures and the patient died within a week. Discussion: Acute panmyelosis with myelofibrosis is not thoroughly studied. Although WHO has classified it as a type of AML, some still consider it equivalent to AMKL or an acute kind of MDS (myelodysplastic syndrome). APMF comprises less than 1% of the cases of AML. The disease typically presents with an acute onset of pancytopenia without any splenomegaly and is rapidly fatal with mean survival of less than a year. Significant differential diagnoses include acute megakaryoblastic leukemia (AML) and acute myeloid leukemia with myelodysplasia-related changes (AML-MRC). AML and APMF share multiple features like fibrotic un-aspirable bone marrow and the presence of megakaryoblasts. However, in AML, most of the blast population comprises megakaryoblasts, while in APMF, non-megakaryocytic cells are predominant. Compared to AML-MRC, abrupt clinical onset and worse survival rate point towards APMF. In addition, multilineage dysplasia led by myelodysplastic syndrome is also characteristic of AML-MRC. Similarly, exposure to leukemogenic therapeutic agents should also be ruled out, as such cases should be categorized as MDS or AML therapy-related diseases. Due to the disease being extremely rare, there are no established management protocols. The most commonly used treatment is with 3 + 7 induction chemotherapy. A retrospective study showed a poor outcome of hematopoietic cell transplantation due to a high relapse rate. Another case showed remission by 3+7 induction with idarubicin and cytarabine followed by cytosine arabinoside. In our case, hospice care was preferred considering the age and comorbidities