BACKGROUND Dermal fillers are used to augment wrinkles and folds, and a variety of hyaluronic acid (HA)-based products are available. The non-animal-sourced HA studied was cross-linked using a two-step process and employing cohesive polydensified matrix (CPM) technology. This HA gel (CPMHA) has variable density and viscosity zones for adaptation in the dermis. OBJECTIVE To compare the safety and effectiveness of CPMHA with that of bovine collagen (COL) in the correction of moderate to severe nasolabial folds (NLFs) in a split-face study. METHODS AND MATERIALS One hundred eighteen subjects were randomized to receive CPMHA and COL on contralateral sides of the face. NLF severity was measured using the Wrinkle Severity Rating Scale (WSRS). The initial treatment was evaluated after 2 weeks, and an optional touch-up to optimal cosmetic correction was permitted if needed. Subjects returned every 2 weeks (up to 24 weeks) for evaluation. Safety was assessed using spontaneous adverse event (AE) reporting. RESULTS CPMHA resulted in a significantly greater reduction in the mean change of WSRS than COL at weeks 8 (p=.009), 12 (p<.001), 16 (p<.001), and 24 (p<.001). There were no significant differences between the two groups in the proportion of AEs considered related to the injection site procedure. Most AEs were mild to moderate in severity and resolved within 7 days. CONCLUSION CPMHA was well tolerated and first demonstrated to be noninferior and then superior in terms of effectiveness to COL over 24 weeks for the treatment of NLF, including the primary end point at week 12. Merz Pharmaceuticals, LLC funded this Food and Drug Administration clinical trial. Bhushan Hardas, Mandeep Kaur, Starr Grundy, and Eric Pappert are employees of Merz Pharmaceuticals.