Patients with Waldenstrom have a high level of a protein called immunoglobulin M (IgM) in their blood. These high levels of IgM can cause a thickening of the blood (hyperviscosity), resulting in symptoms such as nosebleeds, headaches, dizziness, and blurring or loss of vision. Other symptoms may include tiredness, night sweats, headaches, pain or numbness in the extremities, and increased size of the liver, spleen, and lymph nodes. While some patients experience these symptoms, others do not.

To diagnose Waldenstrom, blood and urine tests are usually performed as well as a bone marrow biopsy. During the biopsy, a needle is inserted into a bone (usually the pelvic bone) and a small sample of bone marrow is extracted for examination.

Initially diagnosing waldenstrom's macroglobulinemia can be difficult because there are few initial symptoms, in fact often routine blood work or examinations which return abnormal results provide the first indication. Swollen lymph-nodes, or enlarged organs such as the liver or the spleen may be discovered in a physical examination and could be indicators of waldenstrom's macroglobulinemia.

Blood tests can be used to indicate a number of factors that would lead to a waldenstrom's macroglobulinemia diagnosis. A high level of IgM in the blood stream is a distinguishing feature of the disease. Blood tests could also reveal hyper-viscosity which is a common problem with waldenstrom's macroglobulinemia.

A waldenstrom's macroglobulinemia diagnosis can also be made through the use of a bone marrow biopsy. For this a sample of bone marrow is taken from the patient through a needle which is examined under a microscope for indicators of waldenstrom's macroglobulinemia which are high levels of B-lymphocytes and plasma cells.