BACKGROUND: The different rheological properties of hyaluronic acid (HA) filler reflect their specific manufacturing processes and resultant physicochemical characteristics. However, there are few researches about the relationship between product differences and clinical outcome when HA fillers are used for nasolabial folds (NLFs). AIMS: This study sought to compare the rheological properties, efficacy and safety of a monophasic HA filler, and a well-studied biphasic HA filler, in the treatment of NLFs. PATIENTS/METHODS: A total of 72 Korean subjects with moderate to severe NLFs were randomized to receive injections with monophasic HA or biphasic HA on the left or right side of the face. Efficacy was evaluated by the change in the Wrinkle Severity Rating Scale (WSRS) at 2, 10, 18, 26, and 52 weeks. Safety was assessed on the basis of all abnormal reactions during the clinical test period. To compare the rheological characteristics of two cross-linked HA fillers, viscoelastic analysis was performed. RESULTS: At week 26, the mean WSRS was 2.26±0.56 for the monophasic HA side and 2.24±0.54 for the biphasic HA side. Both treatments were well tolerated. The adverse reactions were mild and transient. Monophasic HA filler had lower elasticity and higher viscosity than biphasic HA filler. CONCLUSION: Despite a number of different rheological properties, monophasic HA is noninferior to biphasic HA in the treatment of moderate to severe NLFs for 52 weeks. Therefore, monophasic HA provides an alternative option for NLFs correction.