The blood and bone marrow constitute the hematologic organ system. Unlike other organ systems, hematologic organs are distributed in space and provide for a variety of seemingly unrelated functions. The hematologic system has both cellular and fluid-phase elements. Cellular elements include erythrocytes, leukocytes, and platelets; fluid phase elements include coagulation factors, natural antithrombotics, and proteins of the fibrinolytic system. The most common abnormalities of the hematologic system in patients with sepsis are anemia, leukocytosis, thrombocytopenia, and activation of the hemostatic system. Dysfunction of the hematologic organ system is an early manifestation of severe sepsis and is seen in virtually all patients with this disease. In concert with alterations in the endothelium, hematologic changes reflect both the body's reaction to an infectious insult as well as attempts to restore homeostasis. Dysfunction of the hematologic organ system can contribute to multiple organ dysfunctions and death. Recognizing these sepsis-associated changes and understanding the underlying pathophysiology are key to improving outcomes in patients with this deadly disease.