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To examine the usage and mutational status of VH genes in hairy cell leukaemia (HCL), we analysed 24 immunoglobulin heavy chain (IgH) sequences expressed in 23 patients. None had premature stop codons. VH3-23 was the most common gene and a VH6 gene was observed for the first time in HCL. Although the mean mutation frequency was 6.1%, slightly higher than in previous HCL series, four patients had 99.6-100% homology to germline sequences, three of whom had high tumour burdens and poor outcomes. Despite the high mutation frequency, only two of 24 rearrangements had clear statistical evidence of antigen-dependent somatic mutation. Our results increase the database of reported functional HCL rearrangements to 94 in 92 patients. Overall, both gene usage and mutation frequency are very similar to mucosa-associated lymphoid tissue-type marginal zone lymphoma. The data are consistent with HCL originating from post-germinal centre marginal zone B cells, although the heterogeneity observed suggests that HCL may originate differently in some patients, and this could have implications for prognosis and treatment.