Follicular lymphoma is characterized by the t(14;18) in up to 85% of cases. Almost all cases display evidence of secondary chromosomal alterations at initial diagnosis. The influence of recurrent secondary changes on disease progression has not been fully determined. The purpose of this study was to define the full spectrum of recurrent karyotypic events present at diagnosis in a large cohort of cases and to evaluate the sequence of cytogenetic evolution in relation to morphologic progression. A total of 165 cases of follicular lymphoma with t(14;18) were ascertained for which complete clinical information, histopathology, immunophenotype, and karyotype were available. One hundred sixty cases showed secondary alterations with an average of 7.9 additional changes per case. Recurrent alterations seen at the 10% or greater level included ϩX, ϩ1q21-q44, ϩ7, ϩ12q, ϩ18q, del(1)(p36), del(6q), del(10)(q22-q24), the development of polyploidy and sidelines, and the presence of extra marker chromosomes and chromosomal additions. Changes that correlated with morphologic progression included del(1)(p36), del(6q), del(10)(q22-q24), ϩ7, the total number of abnormalities, the number of markers and additions, and the presence of polyploidy. The most frequent second event arising after the t(14;18) was duplication of the der(18)t(14;18). This study demonstrates that the number and type of secondary chromosomal alterations in follicular lymphoma is highly variable between cases, but that a relatively small number of changes are seen repeatedly in different combinations. A consistent pattern of cytogenetic evolution could not be identified. Potentially significant gene duplications or amplifications may be disguised within marker chromosomes and additions. Additional cytogenetic investigation is required to decipher the karyotypic complexity associated with the progression of follicular lymphoma.