Analysis of somatic mutation in circulating peripheral blood T cells can be used as an index of in vivo T-cell amplification. The ability to assess the frequency of T cells that survive in vitro in the presence of 6-thioguanine is an index of mutation at the HPRT gene locus. In the absence of exposure to mutational agents, elevations of the HPRT mutant frequency (mF) of T cells reflects errors in DNA replication and repair that have become fixed during the process of cell division. We estimated the mF of T cells in MS patients and controls over a period of 36 months and found that the mF was consistently elevated in MS patients of all clinical subgroups. In the chronic progressive group of MS, the mF increased over a 3-year period and appeared to correlate with the clinical worsening of the disease.