The aim of this study was to quantify and characterise the CD4+ and CD8+, CD45RA+, CD45RO- T-lymphocytes that paradoxically expressed the CD29 bright+ phenotype in health and in rheumatoid arthritis. We further evaluated their clinical implications. Blood samples were obtained from 100 patients with rheumatoid arthritis and 40 age- and sex-matched controls. Cell surface antigens and interleukin-2 (IL-2) binding were detected on CD4+ and CD8+ peripheral blood T-lymphocytes (T-PBL) by three-colour flow cytometry. One-third of the patients were clinically evaluated at the time of blood sampling. In healthy donors, we found 16 ± 14% of CD29 bright+cells among CD4+, CD45RA+, RO-T-PBL. These “false naive” CD4+ T-PBL were Leu-8+, and a majority expressed the CD25/p55 receptor (IL-2Rα chain), while a minority showed the CDlla bright+, CD69+ and/or CD 122/p75+ (IL-2Rβ chain) phenotype, and few cells were CD31 bright+ and HLA-DR+. In rheumatoid arthritis, their proportion among CD4+, CD45RA+, RO- cells increased to 25 ± 15% (P < 0.001, compared with controls). In patients, the reductions in CD31 and CD38 expression (P < 0.05 for both), as well as the enhanced CD25 expression (P < 0.001) on CD4+, CD45RA+, RO- T-PBL reflected a more differentiated phenotype. The occurrences of CD25 and CD122 were increased on false naive CD4+ T-PBL (0.01 <P<0.001); however, the binding of IL-2 remained very low (in contrast to the binding of IL-2 on CD45RO+ T-PBL). Furthermore, a major subset of CD8+, CD45RA+, RO- T-PBL (45 ± 17% in controls) expressed the CD29 bright+ phenotype. These “false naive” CD8+ T-PBL included a great many of CID 1lb+, CD28- cells, while a minority showed the HLA-DR+, CD69+ and/orCD122+ phenotypes. Patients with low levels of IgM rheumatoid factors (IgM-RF; but with active disease) had an elevated proportion of CD45RA+, RO-cells among the CD8+ T-PBL, in part due to an increased proportion of false naive cells (P < 0.05). In patients, the false naive CD8+ T-PBL showed down-regulated CD1lb and an increased expression of IL-2 receptor chains (CD25 and CD 122; 0.05 <P < 0.01), but without a significant increase in IL-2 binding. More CD69 on false naive CD8+ T-PBL was found in patients with high levels of IgM-RF (P < 0.005 compared to patients with low 19M-RF). Finally, both false naive CD4+ and CD8+ T-PBL correlated with the clinical process and outcome variables (0.05 <P <0.01). The levels of activated false naive CD4+ T-PBL (CD25+ and/or CD122+) or CD8+ T-PBL (CD69+ and/or CD122+) were associated with clinical parameters of disease activity (0.05 <P < 0.01). Thus, in rheumatoid arthritis, false naive T-PBL showed important qualitative differences. The levels of activated false naive T-PBL could be particularly interesting for monitoring disease evolution.