The familial occurrence of chronic lymphocytic leukemia was studied using morphologic, immunophenotypic, cytogenetic, and immunoglobulin gene rearrangement analyses. Three of six siblings developed chronic lymphocytic leukemia. One (patient 1) died 9 years after the diagnosis of chronic lymphocytic leukemia at age 67 years. The other two patients, ages 64 and 68 years (patients 2 and 3, respectively), are alive after chronic lymphocytic leukemia was diagnosed 11 and 4 years ago, respectively. Using the Rye classification, patient 2 and patient 3 had Stage I and Stage O disease, respectively. In contrast, patient 1 had Stage IV disease. The bone marrow of patient 2 was 90% cellular, with sheets of mature lymphocytes, and that of patient 3 was 70% cellular, with a nodular pattern of similar cells. Both patients 2 and 3 had normal karyotypes. Immunophenotyping studies revealed that patient 3 had an expanded population of B cells with minimal to no detectable expression of surface immunoglobulins and membrane-bound light chains. In contrast, the B-cell population of patient 2 expressed immunoglobulins M, D, and Kappa light chains. Gene rearrangement studies performed on these two patients revealed different but distinct patterns of heavy chain rearrangement. This may represent an evolution of two different clones of chronic lymphocytic leukemia in this family.