Background: Hyaluronic acid (HA) fillers such as Restylane®, and poly-L-lactic acids such as Sculptra®, are frequently used to correct facial soft-tissue defects. Objectives: To compare the efficacy and safety of AestheFill®, a novel injectable poly-L-lactic acid (PLA), and Restylane®, a well-studied biphasic HA filler, in the treatment of moderate to severe nasolabial folds. Methods: In this multi-center, randomized, evaluator-blinded, comparative study, subjects were randomized for injections with AestheFill® or Restylane® on the both nasolabial folds. Efficacy was determined by calculating the change in the Wrinkle Severity Rating Score (WSRS) relative to baseline. Local safety was assessed on the basis of reported adverse events. Results: At week 24, the mean improvement in WSRS from baseline was 2.09 ± 0.68 for the AestheFill® side and 1.54 ± 0.65 for the Restylane® side. Both injections were well tolerated and the adverse reactions were mild and transient in most cases. Conclusion: AestheFill® provides non-inferior efficacy compared to Restylane® 6 months after being used to treat moderate to severe nasolabial folds.