The first sign of histiocytosis is often a rash on the scalp, similar to cradle cap. There may be a pain in a bone, discharge from the ear, loss of appetite and fever. Sometimes the stomach is swollen and painful. Occasionally, an area of the brain known as the pituitary gland is affected, and this can lead to the child passing large amounts of urine and being very thirsty. Other potential signs and symptoms include: weight loss, jaundice, vomiting, limping, short stature, delayed puberty, mental deterioration, headache, dizziness, seizures, protruding eyeballs, and/or a generalized rash.

The tumors produce a "punched-out" appearance on bone X-rays. Sometimes, children experience spontaneous fractures as a result of these bone lesions. There is often systemic involvement as well, which may affect the whole body and cause rashes, lung problems, gum infiltration, lymph gland swelling, hormonal problems, enlargement of the spleen and liver, and anemia.