MicroRNA-29 is an anti-fibrotic miRNA whose expression is downregulated in multiple fibrotic indications including in cutaneous scars, keloids and burns. Its target genes include numerous collagens and other extracellular matrix molecules, suggesting that restoration of miR-29 expression in a skin wound or at the site of an excised scar could have a therapeutic benefit by reducing scarring and/or preventing scar regrowth. An oligonucleotide mimic of miR-29b (MRG-201) was studied in vivo in mouse, rats and rabbits as well as in vitro in human skin fibroblasts to identify a set of conserved pharmacodynamic biomarkers in the skin. MRG-201 was then evaluated in a Phase 1 double-blinded within-patient randomized clinical trial in 53 normal healthy volunteers (NCT02603224). Expression of miR-29b and its pharmacodynamic biomarkers was assessed in untreated skin incisions and following single or multiple administrations of MRG-201 at the site of a sutured skin incision. miR-29b expression was significantly decreased and direct miR-29 target genes were significantly upregulated with incision alone. Intradermal administration of MRG-201 resulted in a high local concentration of miR-29b with low systemic exposure and good safety/tolerability at all doses tested. Pharmacodynamic activity was seen after MRG-201 treatment: single and multiple doses of MRG-201 reduced collagen mRNA expression as compared to a placebo injected incision in the same subject. Additionally, multiple administrations of MRG-201 reduced fibroplasia as assessed by histopathology (p<0.01). These findings support further investigation of MRG-201 as a novel therapeutic to inhibit scar formation or prevent hypertrophic scar or keloid recurrence following excision.