Richter's syndrome is the transformation of CLL to diffuse large cell lymphoma, which is one of the non-Hodgkin's lymphomas. Laboratory tests usually confirm that the lymphoma originates from the same population of cells as the leukemia. In this case, it is considered a transformation. If the lymphoma arises from different cells, it can be regarded as a secondary cancer arising by chance.

Richter's syndrome is suspected in any CLL patient who shows the onset of otherwise unexplained fever, weight loss, increase in serum lactate dehydrogenase (LDH), localized enlargement of lymph nodes, and enlargement of the liver and spleen. In this situation, biopsy of the newly enlarged lymph nodes is indicated to determine whether or not lymphoma cells are present.

There are no obvious causes for the transformation of CLL to Richter's syndrome, which can affect patients at any stage of CLL, including those in complete remission. The incidence of Richter's transformation, which carries a poorer prognosis than CLL, has been reported at between three and ten percent.