Fibroblasts are heterogeneous with respect to surface markers, morphology, and participation in fibrotic responses. This study was undertaken to determine whether Thy-1⁻ and Thy-1⁺ rat lung fibroblasts, which have distinct and relevant phenotypes, differ in their proliferative responses to platelet-derived growth factor (PDGF) isoforms. Homogeneous populations of Thy-1⁻ and Thy-1⁺ fibroblasts were found to proliferate equally in the presence of PDGF-BB, but PDGF-AA-mediated proliferation occurred only in Thy-1⁻ cells. This differential activity correlated with significantly higher expression of PDGF-α receptor in Thy-1⁻ fibroblasts as shown by immunoblotting, immunofluorescence, and Northern blotting. There was a rapid increase in c-myc mRNA in Thy-1⁻ but not in Thy-1⁺ fibroblasts on stimulation with PDGF-AA and PDGF-BB. The PDGF-α receptor, which mediates signaling by all PDGF isoforms, has been implicated in numerous clinical and experimental forms of fibrosis and regulates lung morphogenesis. Differential expression of the PDGF-α receptor supports distinct roles for Thy-1⁻ and Thy-1⁺ fibroblast populations in developmental and fibrotic processes in the lung.