Our aim was to examine the genetics of clonal evolution in follicular lymphoma (FL) and to identify genetic alterations associated with disease progression. A total of 100 biopsies from 44 patients diagnosed with t(14;18)-positive FL were examined by array comparative genomic hybridization. In 20 patients the patterns of somatic hypermutations (SHMs) in the variable region of heavy chain gene were additionally analyzed. Gain of chromosome X in male samples was a marker for poor outcome (P < .01). Gains involving chromosome 2, 3q, and 5 were exclusively present in FL biopsies from cases with higher grade transformation and were among the copy number alterations (CNAs) associated with inferior survival. Although we noted a trend for increasing genomic complexity in initial versus late FL samples, the overall frequencies of CNAs in initial and late FL biopsies showed a surprisingly stable pattern through the course of the disease. In 27 of cases the initial samples harbored CNAs that were absent in relapse samples, indicating that tumor cell clones at relapse were not direct descendants of initially dominating clones. The pattern of SHMs confirmed parallel development of tumor cell clones in 14 cases. Our findings support the hypothesis of common progenitor cells in FL.