Human leukocyte antigen G (HLA-G) expression is thought to be associated with a tolerance state following solid organ transplantation.In a lung transplant (LTx) recipient cohort, we assessed (1) the role of HLA-G expression as a predictor of graft acceptance, and (2) the relationship between (i) graft and peripheral HLA-G expression, (ii) HLA-G expression and humoral immunity and (iii) HLA-G expression and lung microenvironment.We prospectively enrolled 63 LTx recipients (median follow-up 3.26 years [min: 0.44-max: 5.03]).At 3 and 12 months post-LTx, we analyzed graft HLA-G expression by immunohistochemistry, plasma soluble HLA-G (sHLA-G) level by enzyme-linked immunosorbent assay, bronchoalveolar lavage fluid (BALF) levels of cytokines involved in chronic lung allograft dysfunction (CLAD) and anti-HLA antibodies (Abs) in serum.In a time-dependent Cox model, lung HLA-G expression had a protective effect on CLAD occurrence (hazard ratio: 0.13 [0.03-0.58]; p = 0.008).The same results were found when computing 3-month and 1-year conditional freedom from CLAD (p = 0.03 and 0.04, respectively [log-rank test]).Presence of anti-HLA Abs was inversely associated with graft HLA-G expression (p = 0.02).Increased BALF level of transforming growth factor-β was associated with high plasma sHLA-G level (p = 0.02).In conclusion, early graft HLA-G expression in LTx recipients with a stable condition was associated with graft acceptance in the long term.