A longitudinal study of Ig V gene segments utilized by B cells from the cerebrospinal fluid (CSF) of two patients with multiple sclerosis (MS) was carried out using RT‐PCR methodologies. One patient with a relapsing‐remitting (RR)‐MS was investigated at onset and at relapse, 1 year later. A patient with secondary‐progressive (SP)‐MS was tested 9 and 13 years after disease onset. Sequenceanalyses of V_HDJ_H segments bearing V_H3 and V_H4 that were obtained from Cγ cDNA genes demonstrated a substantial proportion of shared clones in the samples taken at different times; these clones were identical or closely related, i.e. had the same third complementary determining region (CDR) of the H chain variable region gene (HCDR3) with different mutations in the V_H segment. Collectively, these data demonstrate that in MS patients there is a strong selective pressure, which could be exerted by antigen (or autoantigen) stimulation, for the maintenance and partial diversification of certain V_HDJ_H Cγ sequences.