To explore further the role of substance P (SP) in wound healing and scar formation, SP concentrations in wounds of scalded rats were assayed. Expressions of apoptosis-associated genes in fibroblasts cultured with SP were detected. SP concentrations in superficial wounds increased earlier than those in deep wounds. SP was associated with an increased proliferation and a decreased apoptosis of fibroblasts. It had a greater influence on keloid fibroblasts than on hypertrophic scar fibroblasts by elevating the expression of proliferating cell nuclear antigen and BCL-2 in fibroblasts. Spantide completely suppressed the effects of SP on hypertrophic scar fibroblasts, and partly inhibited its effects on keloid scar fibroblasts. SP may play an important role in wound healing by promoting wound fibroblast proliferation and inhibiting apoptosis. It may also participate in pathological scar formation by modulating the expression of apoptosis-associated genes. SP is postulated to play a dual role in wound repair.