Malaria primarily affects the spleen, causing splenomegaly (enlargement of the spleen). The malaria parasite (Plasmodium) infects red blood cells, which are then filtered by the spleen. The spleen becomes enlarged due to increased work in removing infected and damaged red blood cells. While the liver is also involved (malarial parasites initially infect liver cells), splenomegaly is the most characteristic clinical feature of malaria.