Background: Microneedle patch recently have been used to increase skin permeability improving drug delivery and for cosmetic purposes. However, such treatment may fail if skin penetration is insufficient reducing drug delivery or if compliance is reduced by discomfort.Objectives: : To evaluate the efficacy and the safety of microspicules containing epidermal growth factor (MS-EGF) used to treat periorbital wrinkles. Methods: Twenty health volunteers were enrolled in a randomized, controlled, split-face study. One periorbital area was treated daily with soluble MS-EGF and the other with EGF cream, for 4 weeks; all subjects underwent 8 weeks of follow-up. Efficacy was assessed using a wrinkle severity rating scale (WSRS), subjective satisfaction scores, digital skin image analysis, examination of skin replicas, and ultrasonic measurement of dermal depth and density. Results: Both the MS-EGF and EGF alone yielded positive effects on digital skin image analysis, skin replica examination, and ultrasound. However, the MS-EGF groupexhibited significant improvements in dermal depth and density, and on replica analysis, compared to theEGF-only group (P < 0.05). In addition, the MS-EGF group showed a significantly greater change in WSRS score compared to baseline than the EGF-alone group. Both treatments were well-tolerated; no significant side-effect was noted. Conclusion: The MS-EGF formulation may represent an effective and biocompatible advance in the treatment of periorbital wrinkles.