Obliterative bronchiolitis (OB) is a dreaded and frequent complication of lung transplantation with a poorly understood immunopathogenesis. To further evaluate disease mechanisms, we used T cell antigen receptor (TCR) β-chain variable region RNase protection assays, after polymerase chain reaction amplification of TCR cDNA, to quantitate circulating CD4+ and CD8+ repertoires of transplant recipients with OB or no evidence of rejection (NER). All six recipients with OB had markedly abnormal CD4 expansions (2.5 ± 0.5 expansions/recipient) attributable to oligoclonal proliferations. Only two of six recipients with NER had a single, much lesser, CD4+ abnormality each (p < 0.01). Moreover, one of these patients developed OB shortly thereafter, and the other NER abnormality may have predated transplantation. In contrast, CD8+ expansions were common in both recipient populations. Findings of CD4+ expansions had 100% sensitivity and 80% specificity for the presence or imminent development of OB. These data suggest proliferations of CD4+ T cells are important in OB pathogenesis, and these are most likely part of a major histocompatibility complex Class II-dependent process of indirect alloantigen presentation. These CD4+ clones are likely to have facultative helper functions for the multiple and diverse immune processes that have been implicated in OB. Furthermore, the close association of CD4+ expansions with OB raises possibilities of development of novel diagnostic and therapeutic approaches.