In the course of studying the circulating TCR repertoire in humans, we noted several individuals with an increase in the percentage of CD8+ T cells expressing a particular V region. In some cases, these CD8 expansions were dramatic, occupying over 40% of the total CD8 repertoire. Using a panel of mAbs to different TCR V regions, we found that over 30% of healthy adults (> 35 years of age) harbor an expansion that alters the peripheral blood CD8 TCR repertoire. A wide range of V regions were expressed by these expansions. Considering that the mAbs used cover only a portion of the V beta repertoire, the data suggest that over 70% of adults are likely to harbor such expansions. Junctional region sequencing showed that the CD8 subset expansions were clonal, and serial studies as long as 4 years showed that they persisted indefinitely. Expansions were not identified in the CD4 population. Discordant expression of one large V beta 6.7+ clone was found in one identical twin set, suggesting the possibility that an environmental exposure is involved in their generation and/or expansion. In one large family, we found five family members with a large CD8 subset expansion. Remarkably similar usage of J beta regions was noted, and two individuals demonstrated V beta 3-expressing clones with homologous CDR3 regions, differing by only one major substitution. The repertoire data from this family suggest that the T cell clones have arisen in response to a common Ag. Studies of patients with rheumatoid arthritis found a significantly increased frequency of circulating CD8 subset expansions that expressed a different V region repertoire compared with the healthy individuals studied. Overall, our results emphasize a frequent alteration in the human CD8 TCR repertoire, most likely related to an environmental exposure, in both healthy individuals and patients with rheumatoid arthritis. The presence of these expansions will be important to consider in any study of human TCR repertoire, and their implication for health and disease will be important to understand.