Objective · To investigate the intrinsically regulatory role of transcription factor STAT3 on the activation and proliferation of CD8+ T cells in immunodeficient Rag1-/- mice. Methods · The CD8+CD44-CD62L+Na?ve T cells, from CD45.1 wild type (WT) mice and CD45.2-CD8 (ΔStat3) mice, were sorted by flow cytometry cell sorter, equally mixed and labelled with Carboxyl Fluorescein diacetate Succinimidyl Ester (CFSE), and then transferred (i.v.) to the Rag1-/- mice. Ten days after CD8+ T cells transfer, the proportion and proliferation of CD8+ T cells in the spleen, mesenteric lymph nodes (mLNs) and popliteal lymph nodes (pLNs) were determined by flow cytometry. TNF-α, IFN-γ, FasL and granzyme B (GraB) produced by the CD8+ T cells were measured with flow cytometry after PMA and ionomycin stimulation. The statistical significance of activation and effectors expressed between WT and ΔStat3 CD8+ T cell was analyzed by t test. Results · The percentages of WT CD8+ T cells in spleen, mLNs and pLNs were significantly higher than that in ΔStat3 CD8+ T cells (76.2% vs 23.4%, 82.1% vs 17.4%, 64.5% vs 32.3%, with all P=0.008). The percentage and cell number of activated CD44+CD8+ T cells in WT CD8+ T cells were much higher than those in ΔStat3 CD8+ T cells in pLNs (all P=0.008). In spleen, pLNs and mLNs, the levels of TNF-α, IFN-γ, GraB and CD107a expressed in WT CD8+ T cells were higher than those in ΔStat3 CD8+ T cells (all P<0.05). Conclusion · Rag1-/- mice can work as an ideal model to evaluate the survival, proliferation, activation and function of CD8+ T cells in vivo. STAT3 intrinsically regulates the proliferation, activation and function of CD8+ T cells in vivo.