REVIEW ARTICLE Systematic Review of Clinical Trials of Small- and Large-Gel-Particle Hyaluronic Acid Injectable Fillers for Aesthetic Soft Tissue Augmentation JOEL L. COHEN, MD,* † STEVEN H. DAYAN, MD, FACS, ‡§ FREDRIC S. BRANDT, MD, ¶ DIANE B. NELSON, BSN, MPH,** ROBERT A. AXFORD-GATLEY, MD, †† MICHAEL J. THEISEN,PHD, †† AND RHODA S. NARINS, MD ‡‡§§ BACKGROUND Hyaluronic acid (HA) is the most frequently injected filler for soft tissue augmentation in the United States. OBJECTIVE To systematically review published evidence for aesthetic use of small- and large-gel-particle HA. METHODS AND MATERIALS Clinical data on anatomic area, level of evidence, patient population, trial design, endpoints, efficacy, and safety were extracted from PubMed. RESULTS Fifty-three primary clinical reports were analyzed. The highest-quality efficacy evidence was for the nasolabial folds (NLFs), with 10 randomized, blind, split-face, comparative trials. Several randomized, blind trials supported treatment of the glabella, lips, and hands. Lower-level evidence (from studies with nonrandomized, open-label, or retrospective designs) was recorded for the nasojugal folds (tear troughs), upper eyelids, nose, infraorbital hollows, oral commissures, marionette lines, perioral rhytides, temples, and cheeks. Common adverse events (AEs) across anatomic areas were pain, bruising, swelling, and redness. Serious AEs were uncommon (8 events in 8 patients of 4,605 total patients) and were considered to be unrelated (7 events) or probably unrelated (1 event) to treatment. CONCLUSION The efficacy and safety of small- and large-gel-particle HA are well established for NLFs; evidence for the glabella, lips, and hands is more limited. Preliminary reports in other anatomic regions suggest efficacy without major complications. This review was funded by Medicis Aesthetics Inc., Scottsdale, Arizona. Complete Healthcare Communica- tions Inc., Chadds Ford, Pennsylvania, provided editorial support for the development of this manuscript. Drs. Cohen, Dayan, Brandt, and Nairns have served as consultants or clinical trial investigators for Medicis Aesthetics; Ms. Nelson is an employee of Medicis Aesthetics; Drs. Axford-Gatley and Theisen are employees of Complete Healthcare Communications, whose services are funded by Medicis Aesthetics. T he overwhelming majority of aesthetic treat- ments performed in the United States are nonsurgical or minimally invasive aesthetic proce- dures. This represents a dramatic shift from almost 15 years ago. In 1997, 46% of aesthetic procedures were surgical, whereas in 2010, 83% of patient treatment sessions were nonsurgical. 1 Injectable products are used in 52% of these minimally invasive procedures; the rest are mostly chemical, mechanical, or laser techniques to rejuvenate the skin or remove hair. 1 In 2004, the first full year after approval of the first non–animal-based hyaluronic *AboutSkin Dermatology and DermSurgery, Englewood, Colorado; † Department of Dermatology, University of Colorado, Denver, Colorado; ‡ Chicago Center of Facial Plastic Surgery, Chicago, Illinois; § Department of Otolaryngology, University of Illinois, Chicago, Illinois; ¶ Dermatology Research Institute LLC, Coral Gables, Florida; **Medical Affairs, Medicis Pharmaceutical Corporation, Scottsdale, Arizona; †† Complete Healthcare Communications, Inc., Chadds Ford, Pennsylvania; ‡‡ Dermatology Surgery and Laser Center, White Plains, New York, New York; §§ Department of Dermatology, Medical School, New York University, New York, New York © 2012 by the American Society for Dermatologic Surgery, Inc.  Published by Wiley Periodicals, Inc.  ISSN: 1076-0512  Dermatol Surg 2012;1–27  DOI: 10.1111/dsu.12036 1