Excessive production of too many activated immune cells (lymphocytes) called T cells, natural killer cells, B cells, and macrophages (histiocytes) and cytokines by the immune system causes symptoms and damages liver and spleen and causes these organs to enlarge. Familial hemophagocytic lymphohistiocytosis also destroys blood-producing cells in the bone marrow, a process called hemophagocytosis. As a result, affected individuals have low numbers of red blood cells (anemia) and a reduction in the number of blood cells involved in clotting (platelets). A reduction in platelets may cause easy bruising and abnormal bleeding.

The brain may also be affected in familial hemophagocytic lymphohistiocytosis causing various symptoms and complications.

Secondary hemophagocytic lymphohistiocytosis is usually associated with infection by viruses, bacteria, fungi, or parasites or in association with lymphoma, autoimmune disease, or metabolic disease. Acquired HLH may have decreased, normal, or increased NK cell activity.