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Elevated levels of platelet-derived growth factor (PDGF) isoforms in fibrosis are implicated in driving a dysfunctional profibrotic fibroblast phenotype. This study investigated the differential effects of the five PDGF isoforms (AA, AB, BB, CC, and DD) in inducing neonatal dermal and fetal lung fibroblast contraction, proliferation, cytokine production, myofibroblast differentiation, and extracellular matrix (ECM) deposition. All PDGF isoforms, except PDGF-AA, increased contraction of 3-dimensional collagen I gels by dermal (p < 0.01) and lung fibroblasts (p < 0.05) compared to media control. PDGF-AB, BB, and CC enhanced proliferation only in dermal fibroblasts (p < 0.05). PDGF-BB induced profibrotic IL-11 cytokine release in dermal and lung fibroblasts (p < 0.0001) and IL-6 cytokine release in dermal fibroblasts (p < 0.05) compared to media control. None of the PDGF isoforms affected ECM synthesis or myofibroblast differentiation. Dermal fibroblasts exhibited elevated PDGF Receptor-β (PDGFRβ) expression (p < 0.01) and increased basal ERK1/2 phosphorylation (p < 0.05) compared to lung fibroblasts. In summary, PDGF modulates fibroblast functions in a tissue-specific manner, with PDGF-BB driving profibrotic processes in dermal fibroblasts through high PDGFRβ expression and ERK1/2 signalling. Further research is needed to explore the benefit of tissue and isoform-specific PDGF inhibition strategies in skin and lung fibrosis.