The t(14;18)(q32;q21) is a cytogenetic hallmark of follicular lymphoma and also occurs in approximately 20% of diffuse large B-cell lymphomas of follicle center cell origin. Relatively few cases of chronic lymphocytic leukemia/small lymphocytic lymphoma with t(14;18) have been reported previously. We report the clinicopathologic, cytogenetic, and molecular genetic features of 12 patients with chronic lymphocytic leukemia associated with t(14;18). There were 9 men and 3 women, with a median age of 51 years at diagnosis. To date, 11 patients have required chemotherapy, 6 before coming to our institution. At last follow-up, 5 patients have died of disease. Karyotypic analysis showed that 10 cases had t(14;18) in the stemline and 2 cases in the sideline; t(14;18) was the sole abnormality in the stemline in 2 cases. In 11 cases, other abnormalities were identified in the stemline or sidelines, most commonly trisomy 12 in 6 cases. Trisomy 12 was associated with atypical morphology and immunophenotype. Of 8 cases tested, 7 showed somatically mutated immunoglobulin heavy chain variable region genes. We conclude that the t(14;18) in chronic lymphocytic leukemia is associated with relatively young age at diagnosis, mutated immunoglobulin heavy chain variable region genes, and a clinical course that usually requires chemotherapy. The cytogenetic findings, in particular, t(14;18) in the stemline in 10 cases and as the sole karyotypic abnormality in 2 cases, suggest that t(14;18) is an early pathogenetic event in this small subset of chronic lymphocytic leukemia cases.