In cases where hairy cell leukemia is suspected, diagnosing the condition is relatively straight forward.

The diagnosis process involves the following steps:
 

• A detailed history of the patient’s symptoms is obtained and hairy cell leukemia may be suspected if the following clinical features are present:
  • Weakness and fatigue
  • Infection
  • Fever
  • Unexplained weight loss
  • Shortness of breath
  • Lumps in the stomach, groin or under the arms
  • Pain below the ribs
• Up to 90% of patients develop an enlarged spleen or splenomegaly. If the spleen becomes large enough, it may press on other organs in the abdomen.
• A complete blood count usually reveals a low red blood cell count as well as reduced numbers of white blood cells and platelets.
• The hairy cells strongly express CD103, CD22, and CD11c when examined using flow cytometry. They are also abnormally large and express CD19, CD20, CD25 and FMC7. If the patient has hairy cell leukemia-variant, CD25 is not expressed.

Flow cytometry is also performed to exclude other conditions that present with similar symptoms such as aplastic anemia, myelophthisis and other blood cancers such as atypical chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, hypoplastic myelodysplastic syndrome and idiopathic myelofibrosis.

• A bone marrow biopsy is usually required to confirm the diagnosis. The cells are viewed using a stain called tartrate resistant acid phosphatase (TRAP).
• A computed tomography (CT) scan often reveals abdominal lymphadenopathy.