Background: The authors' previous studies with 2 different adult patient populations demonstrated a correlation between indirect allorecognition of mismatched donor HLA Class I- and Class II-derived peptides and the development of bronchiolitis obliterans syndrome (BOS) after lung transplantation. The aim of this study was to determine whether a parallel allorecognition of mismatched donor HLA Class I- and Class II-derived peptides occurs after lung transplantation and to determine its correlation with the development of BOS after lung transplantation in a group of pediatric patients. Methods: Peripheral blood mononuclear cells from 7 BOS-positive and 6 BOS-negative pediatric lung transplant recipients (age, 11.5 ± 4.4 years) were cultured in the presence of synthetic peptides corresponding to the α-chain hypervariable regions of a mismatched donor HLA Class I molecule and the β-chain hypervariable region of a mismatched donor HLA-DR molecule. The frequencies of HLA Class I and Class II alloreactive T cells were determined using limiting dilution analysis. Results: A significant increase (p = 0.025) in HLA Class I-alloreactive T cells was observed in BOS-positive patients (7.1 × 10-5 ± 4.3 × 10-5) compared with BOS-negative patients (2.1 × 10-5 ± 1.8 × 10-6). In addition, a significant increase (p = 0.033) in HLA Class II-alloreactive T cells also was observed in BOS-positive patients (9.6 × 10-5 ± 7.9 × 10-5) compared with BOS-negative patients (1.3 × 10-5 ± 2.1 × 10-6). Conclusions: This study indicates that a parallel CD4+ T-cell alloreactivity to both donor HLA Class I and Class II molecules may play a role in the pathogenesis of BOS both in adult and pediatric lung transplant recipients.