BACKGROUND: Nonablative fractional photothermolysis (FP) laser treatment has shown clinical efficacy on photo-aged skin. Few studies have examined the molecular responses to FP. OBJECTIVE: To characterize the dynamic alterations involved in dermal matrix remodeling after FP laser treatment. METHODS: A single multipass FP treatment was performed. Baseline, day 1, and day 7 biopsies were obtained. Biopsies were sectioned and stained for histology and immunofluorescence confocal microscopic. Heat shock protein-70 (HSP-70) and matrix metalloproteinase-1 (MMP-1) expression and extracellular matrix (ECM) autofluorescence were examined. Quantitative real-time polymerase chain reaction (qRT-PCR) experiments were performed probing for collagen 1A1 (COL1A1) and COL3A1. RESULTS: All three patients were Caucasian women aged 49, 62, and 64 with Fitzpatrick skin types II, III, and IV. Transient neutrophilic infiltration found on day 1. Protein expression of HSP-70 and MMP-1 were up-regulated on day 1, reverting to baseline by day 7. ECM autofluorescence decreased from baseline to day 7. qRT-PCR showed a minor decrease in COL1A1 and COL3A1 messenger RNA 1 day after treatment. Variable results between patients receiving equal treatment were evident.