Background and Objectives: Flashlamp pulsed-dye lasers (PDLs) revealed effective regression or arrest in patients with keloids in our clinical studies [Kuo YR et al., Laser Surg Med 2004;34:104-108]. In this study, we further investigated whether the induction of keloid regression seen with PDL treatment through activation in mitogen-activated protein (MAP) kinase and caspase promotes cell apoptosis and reduces fibroblast proliferation. Study Design/Materials and Methods: Keloid tissues were obtained from 10 patients with intralesional or punch biopsies prior to and 7 days after PDL treatments [fluence per pulse was 10-18 J/cm 2 (mean 14 J/cm 2 )]. Prior to and after PDL treatments, the proliferating fibroblasts in keloid tissue were immunohistochemically detected by proliferating cell nuclear antigen (PCNA) expression. The apoptotic cell was detected by terminal deoxynucleotidyl transferase dUTP-nick end labeling (TUNEL) staining and fragmented caspase-3 expression. MAP kinase activation as represented by extracellular signal-regulated kinase (ERK), p38 kinase (p38), and c-Jun N-terminal kinase (JNK) expression of keloid tissues was investigated by immunohistochemical (IHC) staining, respectively. Results: IHC staining indicated that PCNA expression of fibroblasts was significantly reduced in keloid tissue after PDL irradiation. TUNEL assay revealed lower apoptotic cells expression in the keloid tissue prior to laser treatment. Following laser treatment, apoptotic cells with relatively strong DNA damage and fragmentation were seen in all keloid biopsy samples, especially in the keloid fibroblast population. The activation of ERK and p38 MAP kinase increased significantly in keloid tissue after PDL treatment. JNK was shown to be unchanged. Conclusions: The PDL treatment is shown to induce keloid regression through suppression of keloid fibroblast proliferation, induction of apoptosis, and upregulation of ERK and p38 MAP kinase activity. Lasers Surg.